AU2008307268A1 - Inhaled aztreonam lysine for the treatment of deficits in health-related quality-of life in lung diseases - Google Patents

Description

WO 2009/045706 PCT/US2008/076431 Inhaled Aztreonam Lysine for the Treatment of Deficits in Health related Quality-of-Life in Lung Diseases 5 This is an International Application filed under 35 U.S.C. 361 claiming the benefit under 35 U.S.C. 119(e) to provisional applications 60/997,072 filed October 1, 2007 and 60/997,071 filed October 1, 2007, each of which is incorporated by reference in their entirety. 10 Field of Invention The instant invention relates to the treatment, prevention, and improvement of the health-related quality-of-life (HRQOL) symptoms of lung diseases comprising the 15 administration of aztreonam lysine for inhalation (AZLI). Background Cystic fibrosis (CF) is the most common life-shortening genetic disorder in 20 Caucasians with approximately 70,000 people affected worldwide. CF is a multisystem disease affecting the respiratory tract, the digestive system and the genito-urinary system. The major focus of treatment is the respiratory tract since, by age 24, nearly 80% of patients with CF have chronic Pseudomonas aeruginosa (PA) airway infection, which is associated with an accelerated decline in pulmonary 25 function and is a significant predictor of mortality (2005 Annual Data Report to the Center Directors, Bethesda, Maryland, Cystic Fibrosis Foundation, Bethesda, MD 2006; Pamukcu, A, Pediatr. Pulmonol. 1995; 19:10-5; Henry, RL, Pediatr. Pulmonol. 1992; 12:158-61). Clinical management of CF has improved during the past 15 years. Increased 30 standardization of care and a focus on maintenance therapies, including nutrition, combined with the introduction of dornase alfa in 1993, tobramycin inhalation solution (TIS)(TOBI*) in 1998, and widespread use of chronic azithromycin during WO 2009/045706 PCT/US2008/076431 the past five years have been associated with approximately an 8-year increase in median predicted survival age (to 36.5 years; 1990-2005) and an increase in median forced expiratory volume in I second (FEVI) percent predicted of approximately 10% across all age groups (1990-2005)(Clement, A, Thorax 2006; 61:895-902; Gibson, 5 RL, Am. J. Respir. Crit. Care Med. 2003; 168:918-51). Conventional measures of clinical improvement in CF, such as FEV and bacterial sputum density, that are directed exclusively to respiratory effects of the treatments, do not capture the broader impact of CF on a patient's physical, social, and emotional functioning and may also miss the effects of treatment on other 10 systems that may be affected by the disease. These additional aspects of many lung diseases are measured with health-related quality-of-life (HRQOL) instruments that have been developed for CF, asthma, and other lung diseases (Chang, JA, Chest 1999, 116, 1175-1182; Juniper, E, Am. Rev. Respir. Dis., 1993, 147, 832-838; Henry, B, Qual. Life Res., 2003, 12, 63-76). These measurements reflect an individual's 15 subjective evaluation of his or her daily functioning and well-being, i.e., patient centered evaluation rather than physician centered evaluation. In chronic diseases, some treatments may produce benefits in activities of daily living that are not reflected in conventional medical measurements. For instance, clinical interventions to increase calorie intake to produce changes in weight and height in young children 20 may increase energy levels and the ability to participate in sports in some individuals. Such an outcome is often more exciting for the families than simple weight or height gains. A patient's perception of improvements in daily functioning may also increase adherence to complex and time-consuming treatment regimens for some individuals. In addition, HRQOL instruments provide a basis for evaluating the effectiveness of 25 treatments that are time-consuming and use significant health care resources. This latter effect is important for comparing the cost-effectiveness of different treatments that can influence access to the treatments and reimbursement policies for the treatments. Therefore, there is a need to develop drugs that improve the scores of the HRQOL in patients with lung diseases irrespective of the conventional clinical 30 measurements that may be differentially affected by treatment with the same or a different drug. 2 WO 2009/045706 PCT/US2008/076431 Effects on quality-of-life symptoms of CF can be measured with HRQOL instruments such as the CF Questionnaire-Revised (CFQ-R) (Quittner, Chest 2005, 128, 2347-2354). Disease-related quality-of-life symptoms of CF include eating and digestive disturbances, emotional and physical dysfunction, diminished health 5 perceptions, respiratory disturbances, role/school dysfunction, diminished vitality, diminished social functioning, diminished weight, and other measures of quality of life such as increased treatment burden. These disease-related symptoms are of particularly relevance for patients with CF, who must adhere to complex, time consuming medical regimens that affect their normal activities. Their perception of 10 treatment benefit is likely to improve adherence to treatment regimens and influence their long-term health outcomes as measured by conventional clinical measurements as well as improve the cost effectiveness of their treatment choices (Modi, AC, Pediatr. Pulmonol. 2005; S28:371). Therefore, there is a need for therapies that generally improve the scores of the HRQOL of CF patients. 15 Aztreonam lysine for inhalation (AZLI) is a dry powder or aerosolized formulation of the monobactam antibiotic, aztreonam, and lysine (Montgomery, US patents 6,660,249, 7,138,419, 7208,141, 7,214,364, US patent applications 11/732,234 and 11/729,698; each of which is incorporated by reference in their entirety). In the clinic, AZLI improved the clinical symptoms of CF including FEV 1 , 20 sputum Pseudomonas aeruginosa concentrations and the time to need for inhaled or intravenous antibiotics (Gilead press releases, December 19, 2006 and April 19, 2007; McCoy, K.; et al., 30 th European Cystic Fibrosis Conference June 13-16, 2007, Poster 40, Antalya, Turkey). 25 Summary of Invention It has now been unexpectedly discovered that administration of AZLI to CF patients will improve their HRQOL scores. In a clinical trial described herein, cystic fibrosis patients that had been previously treated with prescribed courses of 30 tobramycin inhalation solution (TIS) for pulmonary Pseudomonas aeruginosa infections were administered a 28 day course of TIS. The study evaluated how these patients responded to symptom domaines of the CFQ-R. At the end of the 28 day 3 WO 2009/045706 PCT/US2008/076431 study, the mean CFQ-R-respiratory domain scores of the patients had decreased -1.47 points, indicating a worsening of this CFQ-R symptom domain, while the other conventional measures of clinical efficacy, FEV 1 and Pseudomonas aeruginosa (PA) sputum concentrations, had improved. Subsequently, these patients were enrolled in a 5 double-blind, placebo-controlled study to evaluate the effects of AZLI on all of these same clinical effects over a 28 day course. In contrast to the TIS study, robust increases in the CFQ-R-respiratory domain scores were produced in the AZLI treated patients. The improvements in FEVI and Pseudomonas aeruginosa (PA) sputum concentrations in the AZLI treated patients were comparable to those reported in the 10 registration trials for inhaled tobramycin ( Ramsey, BW, New Engl. J. Med. 1999, 340, 23-30). Therefore, AZLI and TIS can produce comparable effects on conventional clinical measurements such as FEVI and PA sputum density but AZLI caused improvements in the scores of the CFQ-R not produced by antibacterial drugs such as TIS. 15 This clinical trial also demonstrated that there was only a modest to poor correlation between increases in CFQ-R respiratory scores and FEVI among patients being treated with AZLI indicating that AZLI is unexpectedly treating the patient's perception of the disease. This is a new and unexpected use for AZLI in the treatment of CF and lung disease and the poor correlation between a conventional clinical 20 endpoint (FEV 1 ) and the increased CFQ-R scores shows that AZLI treats another component of lung disease that is separate from that measured by conventional clinical endpoints. In a second randomized, double-blind, placebo-controlled clinical trial described herein, AZLI was administered for 28 days to cystic fibrosis patients that 25 had not been intensively treated with other inhaled antibiotics. Both the conventional clinical parameters used in the trial discussed above and the CFQ-R symptom domains were evaluated in this study. Increases in the scores of eleven of the twelve CFQ-R symptom domains were seen in the AZLI treated patients compared to baseline and the scores in all twelve domains were higher than those in the placebo 30 group. This demonstrates that AZLI produces increases in CFQ-R scores in cystic fibrosis patients that have not been intensively treated with other inhaled antibiotics. 4 WO 2009/045706 PCT/US2008/076431 This second clinical trial also demonstrated that AZLI is treating another feature of lung disease that is separate from that measured by conventional clinical endpoints. As in the first clinical trial, there was only a modest to poor correlation between increased CFQ-R respiratory scores and FEV 1 among patients being treated 5 with AZLI indicating that AZLI is treating the patient's perception of the disease. In addition, the effect on the CFQ-R respiratory domain in this second clinical trial persisted for at least two weeks after discontinuation of the AZLI administration whereas the conventional clinical measure of effectiveness, PA sputum density, had returned to pretreatment concentrations. This again demonstrates a new and 10 unexpected use for AZLI in the treatment of cystic fibrosis and lung disease and the poor correlation between a conventional clinical endpoint (FEV 1 ) and the CFQ-R effect and the persistence of the CFQ-R effect when PA density has returned to pretreatment levels shows that AZLI treats another feature of lung disease that is separate from that measured by conventional clinical endpoints. 15 In a third, open-label, clinical trial described herein, patients from the two trials discussed above were treated with multiple 28-day courses of AZLI alternating with 28 day drug holidays. Conventional clinical parameters used in the trials discussed above and the CFQ-R respiratory domain were evaluated in this study. AZLI consistently produced increases in the CFQ-R respiratory domain scores during 20 each of the treatment periods demonstrating that AZLI produces sustainable effects on HRQOL in cystic fibrosis patients over multiple courses of treatment. Also unexpected, during the 28 day drug holidays, the CFQ-R respiratory domain scores did not decrease to the base line levels seen when the patients entered the study showing that the effects of AZLI persist long after the discontinuation of drug 25 treatment. The sustained increases in CFQ-R scores over multiple cycles of treatment is in contrast to the effects on the conventional measures of clinical efficacy, lung function (FEVI) and PA sputum density, where there is an attenuated response after multiple cycles. The attenuated FEVI and PA sputum density responses over multiple cycles were expected with an antibiotic treatment since in the TSI registration trials, 30 lung function and bacterial density changes were attenuated by the third on cycle of treatment. This further distinguishes the CFQ-R effects of AZLI from its antibiotic effects and shows that AZLI unexpectedly treats another feature of cystic fibrosis and 5 WO 2009/045706 PCT/US2008/076431 lung disease that is separate from that measured by lung function and bacterial density in sputum. The difference seen between the twice daily and three times daily treatment with AZLI is also unexpected. The increase in CFQ-R respiratory domain scores by 5 the third treatment cycle is maintained in the three times daily group, but is greatly attenuated in the twice daily group. This is unexpected and is the first time a regimen response has been seen in a CF inhaled antibiotic trial. Therefore, AZLI produces unexpected HRQOL clinical effects not produced by other inhaled antibacterial drugs in cystic fibrosis patients. These HRQOL effects 10 persist even after discontinuation of the AZLI treatment when conventional measures of clinical efficacy have returned to pretreatment levels and the HRQOL effects are sustained over multiple courses of treatment when responses to conventional clinical measures are attenuated demonstrating that AZLI treats features of cystic fibrosis and lung disease that is separate from its antibacterial effects. 15 The object of the instant invention is to provide a method for preventing, ameliorating, or therapeutically treating at least one or more of the health-related quality-of-life symptoms of a lung disease, in a patient in need thereof, comprising administering aztreonam lysine by inhalation. Non-limiting examples of lung disease include asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, 20 bronchiectasis, ventilator associated pneumonia, asthma, emphysema, chronic bronchitis, and idiopathic pulmonary fibrosis. Brief Description of the Figures 25 Figure 1. Study Design and Patient Disposition for Clinical Trial I. Patients were randomly assigned to treatment with AZLI/placebo before they all began the open-label TIS run-in; their reasons for discontinuing during the TIS run-in are displayed by randomization group. The 211 patients remaining in the study at baseline (Day 0) received at least one dose of AZLI/placebo and comprise the intent 30 to treat (ITT) population. Figure 2. Time to Need for Additional Inhaled or IV Antipseudomonal Antibiotics to Treat Symptoms Indicative of Pulmonary Exacerbation. Data were 6 WO 2009/045706 PCT/US2008/076431 censored for patients discontinuing the study for reasons other than need for additional antibiotics to treat a predefined list of symptoms (decreased exercise tolerance, increased cough, increased sputum/chest congestion, or decreased appetite). The median time to antibiotic need is shown for both treatment groups (AZLI vs. 5 placebo, P =0.007). Figure 3. Changes in Mean CFQ-R-Respiratory Scores, FEVi, and PA Density in Sputum. Child, teen, and adult CFQ-R-Respiratory scores were combined. The CFQ-R was not administered on Day 42. For CFQ-R-Respiratory, at Day 28, P=0.021 for AZLI-BID vs. placebo and P=0.092 for AZLI-TID vs. placebo. For 10 FEV at Day 28, P=0.006 for AZLI-BID vs. placebo and P=0.005 for AZLI-TID vs. placebo. For PA Density (logio PA CFU/gram sputum) at Day 28, P=0.0 11 for AZLI BID vs. placebo and P=0.031 for AZLI-TID vs. placebo. Figure 4. Observed Percentage Change in FEV 1 . Patients were randomly assigned to treatment groups at Day -28, and all three treatment groups received TIS 15 during the open-label, TIS run-in period. AZLI/placebo treatment began on Day 0. Figure 5. Day 28 Percentage Change from Baseline FEV 1 vs. Day 28 Change from Baseline CFQ-R-Respiratory Scores for Individual Patients in the AZLI-BID, AZLI-TID, and Placebo Treatment Groups. Figure 6. Study Design and Patient Disposition for Clinical Trial II. 20 Figure 7. Adjusted Mean CFQ-R-Respiratory Scores, FEVI, and Sputum PA Density: Change from Baseline to Study End (Days 0-42). Child, teen, and adult responses were combined for CFQ-R-Respiratory scores. Figure 8. Change from Baseline to End of Treatment for CFQ-R-Respiratory Scores and FEV 1 : Effects of Age and Baseline CF Lung Disease Severity. The 25 number of patients included in analyses: all patients: AZLI, 80; placebo, 83/84; disease severity-moderate: AZLI, 50; placebo, 53/54; disease severity-severe: AZLI, 30; placebo, 30; age <18 years: AZLI, 21; placebo, 16; age 18 years: AZLI, 59; placebo, 67/68. Figure 9. Change in CFQ-R Respiratory Symptoms Domain Scores during 28 30 Day AZLI Treatment Courses. Figure 10. Mean Relative Change in FEV 1 % Predicted over 28-day AZLI Treatment Courses. 7 WO 2009/045706 PCT/US2008/076431 Detailed Description of the Invention CFQ-R description The CFQ-R is a validated health-related quality-of life measure that meets recent FDA draft guidelines on patient-reported outcomes (Henry, B., QuaL Life Res. 5 2003, 12:63-76; Quittner, A.L., Chest, 2005, 128:2347-54; Modi A.C., J. Ped. Psychol. 2003, 28:535-46; Quittner, A.L., Cystic Fibrosis Foundation. CFQ-R cystic fibrosis questionnaire: a health-related quality of life measure, 2000). The domains include physical, vitality, emotion, eating, treatment burden, health perception, social, body image, role/school, weight, respiratory, and digestion. The number of domains 10 varies depending on the CFQ-R format being used. The four formats of the questionnaire used to collect the data on the eCRF are: Self-administered: * Children ages 6 to 13 (to be completed by the parent or caregiver, self-report format) 15 * Children ages 12 and 13 (to be completed by the child) * Adolescents and adults ages 14 and above (to be completed by the patient) Interviewer-administered: * Children 6 to 11 (to be completed by the research nurse or study coordinator, interviewer format) 20 For children, the interviewer-administered format (ages 6 to 11) and the questionnaire completed by the child (for ages 12 and 13) are identical. For the purpose of reporting, the results from these two formats will be combined and referred to as "Child" version. Questions associated with each domain in each CFQ-R version are shown in Table 1. 8 WO 2009/045706 PCT/US2008/076431 Table 1. CFQ-R Questions in Each Domain Domain Version Parent/caregiver Child Teen/Adult Physical 1-5, 13-16 1-6 1-5, 13, 19-20 Vitality 8-12 - 6, 9-11 Emotion 6-7, 23, 25-26 7-14 7-8, 12, 31, 33 Eating 17,44 15,17,19 14,21,50 Treatment Burden 18, 30-31 16,18,30 15-17 Health Perceptions 22, 24, 32 - 18, 32, 34 Social - 20-26 22-23, 27-30 Body Image 19-21 27-29 24-26 Role/School 27-29 - 35-38 Weight 33 - 39 Respiratory 34-36, 38-40 31-34 40-42, 44-46 Digestion 41-43 35 47-49 Scaled scores for each CFQ-R domain will be calculated as follows: The response (score) of each question will be allocated as 1 to 4 in the order in 5 which they appear on the CFQ-R. For questions with an assigned number designated for each specific response, that number will be the response score. Parent/caregiver version, Question 37 (SAS Program Codes for Scoring the CFQ-R Parent/caregiver Version, CFQ-R handbook [Section 13.3.2]) and Teen/Adult version, Question 43 (SAS Program Codes for Scoring the CFQ-R Teen/Adult 10 Version, CFQ-R handbook [Section 13.3.2]) will not be part of the relevant domain score. The responses of the questions in Table 2 will be reverse scored: Table 2. CFQ-R Reversed Scores Version Questions with Scores Reversed Parent/Caregiver 6, 10, 12, 15, 22, 24, 28, 31, 32 Child 1, 2, 3, 4, 5, 14, 18, 19, 20, 22, 24, 26 Teen/Adult 6, 10, 13, 15, 17, 18, 23, 28, 30, 32, 34, 35 i.e., for the above question responses, a score of 1 will be set to 4, a score of 2 will 15 be set to 3, a score of 3 will be set to 2, and a score of 4 will be set to 1. If participants skip a question, the response will be set to missing. Missing values will be imputed with the median value of all completed responses in the relevant domain. If the median is not an integer in the case of a tie, the value will be set to 9 WO 2009/045706 PCT/US2008/076431 the lower integer, for example a median of 2.5 should be set to 2. If more than half of the responses in a particular domain are missing, no values will be imputed and no domain score will be calculated. The scaled domain score will be calculated (if at least half the domain responses 5 are non-missing) as: 100 Sum of responses in domain - number of questions in domain (n) Maximum possible sum for domain (4n) -n Aspects of the Invention 10 In one aspect, the invention provides a method of treating at least one of the health-related quality-of-life symptoms of a lung disease, in a patient in need thereof, comprising administering a therapeutically effective amount of an inhalable dry powder or aerosol comprising about 1 to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space. 15 In another aspect, the invention provides a method of treating at least one of the health-related quality-of-life symptoms of a lung disease, in a patient in need thereof, comprising administering a therapeutically effective amount of an inhalable dry powder or aerosol comprising about I to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space wherein the dose of inhalable 20 dry powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 consecutive days provided that the total daily dose does not exceed 750 mg per day. In another embodiment of this aspect, the patient has a chronic pulmonary bacterial infection caused by gram-negative bacteria. In one embodiment of this aspect, the inhalable aerosol comprises about 1 to about 250 mg of aztreonam lysine dissolved in 25 about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In another embodiment of this aspect, the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising mass median aerodynamic diameters (MMAD) of about 1 to 30 about 5 pm. In another embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each dose comprises about 1 to about 10 WO 2009/045706 PCT/US2008/076431 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pm. In a preferred embodiment of this 5 aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam. In another preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in 1 mL of saline comprising about 0.17%, w/v, sodium chloride 10 and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particles sizes comprising MMAD of about 1 to about 5 pim. In a particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in 1 mL of saline comprising about 0.17%, w/v, sodium chloride and 15 delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 4m. In another particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day for at least 14 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in I mL of saline comprising about 0.17%, w/v, 20 sodium chloride and is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 4m. In another aspect, the invention provides a method of treating at least one of the health-related quality-of-life symptoms of cystic fibrosis, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount 25 of an inhalable dry powder or aerosol comprising about 1 to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space. In another aspect, the invention provides a method of treating at least one of the health-related quality-of-life symptoms of cystic fibrosis, in a patient in need thereof, comprising administering a therapeutically effective amount of an inhalable 30 dry powder or aerosol comprising about 1 to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space wherein a dose of inhalable dry powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 11 WO 2009/045706 PCT/US2008/076431 consecutive days provided that the total daily dose does not exceed 750 mg per day. In one embodiment of this aspect, the inhalable aerosol comprises about 1 to about 250 mg of aztreonam lysine dissolved in about I to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another 5 embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In another embodiment of this aspect, the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pm. In another embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day provided that a total dose of 10 aztreonam lysine is not higher than about 750 mg a day. In another embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each dose comprises about 1 to about 250 mg of aztreonam lysine dissolved in about I to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an electronic nebulizer adapted to deliver 15 predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 Pim. In a preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam. In another preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose 20 comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pam. In a particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day wherein each inhalable aerosol dose 25 comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 ptm. In another particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day for at least 14 consecutive days wherein each 30 inhalable aerosol dose comprises about 75 ing of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes 12 WO 2009/045706 PCT/US2008/076431 comprising MMAD of about I to about 5 im. In another particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day for at least 28 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, 5 w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 jim. In another aspect, the invention provides a method of treating one, two, three, four, five, six, seven, eight, nine, ten, eleven or all of the symptom domains of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising 10 administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space. In another aspect, the invention provides a method of treating one, two, three, four, five, six, seven, eight, nine, ten, eleven or all of the symptom domains of the CF 15 Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space wherein the dose of inhalable dry powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 consecutive days provided that 20 the total daily dose does not exceed 750 mg per day. In one embodiment of this aspect, the inhalable aerosol comprises about 1 to about 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In another embodiment of this aspect, the 25 inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 [im. In another embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day provided that a total dose of aztreonain lysine is not higher than about 750 mg a day. In another embodiment of this aspect, a dose of inhalable aerosol is 30 administered three to ten times a day wherein each dose comprises about I to about 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an 13 WO 2009/045706 PCT/US2008/076431 electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pAm. In a preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam. In another 5 preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 pim. In a particularly 10 preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day wherein each inhalable aerosol dose comprises 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 pm. In another particularly preferred 15 embodiment of this aspect, a dose of inhalable aerosol is administered three times a day for at least 14 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 1Am. In 20 another particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day for at least 28 days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD 25 of about 1 to about 5 1Am. In another aspect, the invention provides a method of treating the respiratory symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonam lysine per one 30 dose to the airways of the lung endobronchial space. In another aspect, the invention provides a method of treating the respiratory symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need 14 WO 2009/045706 PCT/US2008/076431 thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space wherein a dose of inhalable dry powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 consecutive 5 days provided that the total daily dose does not exceed 750 ing per day. In one embodiment of this aspect, the inhalable aerosol comprises about I to about 250 mg of aztreonam lysine dissolved in about I to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In 10 another embodiment of this aspect, the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pm. In another embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each dose comprises about I to about 250 mg of aztreonam lysine dissolved in about I to about 5 mL of a saline 15 solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 jsm. In a preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam. In another 20 preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pAm. In a particularly 25 preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pm. In another particularly preferred 30 embodiment of this aspect, a dose of inhalable aerosol is administered three times a day for at least 28 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, 15 WO 2009/045706 PCT/US2008/076431 w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 pim. In another embodiment of this aspect, the respiratory symptom domain score is increased by at least 5 points compared to the score at the beginning of the administration. 5 In another aspect, the invention provides a method of treating the body image symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about I to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space. 10 In another aspect, the invention provides a method of treating the body image symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about I to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space wherein the dose of inhalable dry 15 powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 consecutive days provided that the total daily dose does not exceed 750 mg per day. In one embodiment of this aspect, the inhalable aerosol comprises about 1 to about 250 mg of aztreonam lysine dissolved in about I to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another 20 embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In another embodiment of this aspect, the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 pm. In another embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each dose comprises about 1 25 to about 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 pim. In a preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein 30 each inhalable aerosol dose comprises about 75 mg of aztreonam. In another preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of 16 WO 2009/045706 PCT/US2008/076431 aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 ptm. In a particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three 5 times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pm. In another particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a 10 day for at least 28 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pam, In another aspect, the invention provides a method of treating the digestion 15 symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space. In another aspect, the invention provides a method of treating the digestion 20 symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space wherein the dose of inhalable dry powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 consecutive 25 days provided that the total daily dose does not exceed 750 mg per day. In one embodiment of this aspect, the inhalable aerosol comprises about 1 to about 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In 30 another embodiment of this aspect, the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 jm. In another embodiment of this aspect, a dose of inhalable 17 WO 2009/045706 PCT/US2008/076431 aerosol is administered three to ten times a day wherein each dose comprises about 1 to about 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes 5 comprising MMAD of about I to about 5 pim. In a preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam. In another preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of 10 aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 pim. In a particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam 15 dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 ptm. In another particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day for at least 28 consecutive days wherein each inhalable aerosol dose comprises 20 about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 in. In another aspect, the invention provides a method of treating the eating symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need 25 thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about I to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space. In another aspect, the invention provides a method of treating the eating symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need 30 thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space wherein the dose of inhalable dry 18 WO 2009/045706 PCT/US2008/076431 powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 consecutive days provided that the total daily dose does not exceed 750 mg per day. In one embodiment of this aspect, the inhalable aerosol comprises about I to about 250 mg of aztreonam lysine dissolved in about I to about 5 mL of a saline solution 5 comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In another embodiment of this aspect, the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 ptm. In another embodiment of this aspect, a dose of inhalable 10 aerosol is administered three to ten times a day wherein each dose comprises about I to about 250 mg of aztreonam lysine dissolved in about I to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 4m. In a preferred embodiment of this 15 aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam. In another preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium 20 chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 pm. In a particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride and 25 delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 ptm. In another particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day for at least 28 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, 30 w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 pim. 19 WO 2009/045706 PCT/US2008/076431 In another aspect, the invention provides a method of treating the emotional symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonam lysine per one 5 dose to the airways of the lung endobronchial space. In another aspect, the invention provides a method of treating the emotional symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonam lysine per one 10 dose to the airways of the lung endobronchial space wherein the dose of inhalable dry powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 consecutive days provided that the total daily dose does not exceed 750 mg per day. In one embodiment of this aspect, the inhalable aerosol comprises about I to about 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution 15 comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In another embodiment of this aspect, the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 min. In another embodiment of this aspect, a dose of inhalable 20 aerosol is administered three to ten times a day wherein each dose comprises about I to about 250 mg of aztreonam lysine dissolved in about I to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 4m. In a preferred embodiment of this 25 aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam. In another preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonain dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium 30 chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pim. In a particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three 20 WO 2009/045706 PCT/US2008/076431 times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pam. In another particularly preferred 5 embodiment of this aspect, a dose of inhalable aerosol is administered three times a day for at least 28 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 p±m. 10 In another aspect, the invention provides a method of treating the health perceptions symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space. 15 In another aspect, the invention provides a method of treating the health perceptions symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about I to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space wherein 20 the dose of inhalable dry powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 consecutive days provided that the total daily dose does not exceed 750 mg per day. In one embodiment of this aspect, the inhalable aerosol comprises about 1 to about 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another 25 embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In another embodiment of this aspect, the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 tm. In another embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each dose comprises about 1 30 to about 250 mg of aztreonam lysine dissolved in about I to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes 21 WO 2009/045706 PCT/US2008/076431 comprising MMAD of about 1 to about 5 im. In a preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam. In another preferred embodiment of this aspect, a dose of inhalable aerosol is administered three 5 to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 Im. In a particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three 10 times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 4m. In another particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a 15 day for at least 28 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pim. In another aspect, the invention provides a method of treating the physical 20 symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about I to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space. In another aspect, the invention provides a method of treating the physical 25 symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space wherein the dose of inhalable dry powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 consecutive 30 days provided that the total daily dose does not exceed 750 mg per day. In one embodiment of this aspect, the inhalable aerosol comprises about 1 to about 250 mg of aztreonam lysine dissolved in about I to about 5 mL of a saline solution 22 WO 2009/045706 PCT/US2008/076431 comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In another embodiment of this aspect, the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD 5 of about 1 to about 5 pLm. In another embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each dose comprises about I to about 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes 10 comprising MMAD of about I to about 5 tm. In a preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam. In another preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of 15 aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pm. In a particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam 20 dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 pm. In another particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day for at least 28 consecutive days wherein each inhalable aerosol dose comprises 25 about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 ptm. In another aspect, the invention provides a method of treating the role/school symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need 30 thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space. 23 WO 2009/045706 PCT/US2008/076431 In another aspect, the invention provides a method of treating the role/school symptom domain of the CF Question aire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about I to about 250 mg of aztreonam lysine per one 5 dose to the airways of the lung endobronchial space wherein the dose of inhalable dry powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 consecutive days provided that the total daily dose does not exceed 750 mg per day. In one embodiment of this aspect, the inhalable aerosol comprises about I to about 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution 10 comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In another embodiment of this aspect, the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 um. In another embodiment of this aspect, a dose of inhalable 15 aerosol is administered three to ten times a day wherein each dose comprises about I to about 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pim. In a preferred embodiment of this 20 aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam. In another preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium 25 chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 in. In a particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride and 30 delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 min. In another particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a 24 WO 2009/045706 PCT/US2008/076431 day for at least 28 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 im. 5 In another aspect, the invention provides a method of treating the social symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about I to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space. 10 In another aspect, the invention provides a method of treating the social symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about I to about 250 ng of aztreonam lysine per one dose to the airways of the lung endobronchial space wherein the dose of inhalable dry 15 powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 consecutive days provided that the total daily dose does not exceed 750 mg per day. In one embodiment of this aspect, the inhalable aerosol comprises about I to about 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another 20 embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In another embodiment of this aspect, the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 pm. In another embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each dose comprises about 1 25 to about 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pn. In a preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein 30 each inhalable aerosol dose comprises about 75 mg of aztreonam. In another preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of 25 WO 2009/045706 PCT/US2008/076431 aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pm. In a particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three 5 times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pLm. In another particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a 10 day for at least 28 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 4m. In another aspect, the invention provides a method of treating the treatment 15 burden symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonain lysine per one dose to the airways of the lung endobronchial space. In another aspect, the invention provides a method of treating the treatment 20 burden symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about I to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space wherein the dose of inhalable dry powder or aerosol is administered 3 to 10 times a day for at least 14 to 25 28 consecutive days provided that the total daily dose does not exceed 750 mg per day. In one embodiment of this aspect, the inhalable aerosol comprises about 1 to about 250 mg of aztreonam lysine dissolved in about I to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In 30 another embodiment of this aspect, the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pm. In another embodiment of this aspect, a dose of inhalable 26 WO 2009/045706 PCT/US2008/076431 aerosol is administered three to ten times a day wherein each dose comprises about 1 to about 250 mg of aztreonam lysine dissolved in about I to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes 5 comprising MMAD of about 1 to about 5 jim. In a preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam. In another preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of 10 aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 jIm. In a particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam 15 dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 pm. In another particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day for at least 28 consecutive days wherein each inhalable aerosol dose comprises 20 about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 jim. In another aspect, the invention provides a method of treating the vitality symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need 25 thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about I to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space. In another aspect, the invention provides a method of treating the vitality symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need 30 thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about I to about 250 mg of aztreonam lysine per one dose to the airways of the lung endobronchial space wherein the dose of inhalable dry 27 WO 2009/045706 PCT/US2008/076431 powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 consecutive days provided that the total daily dose does not exceed 750 mg per day. In one embodiment of this aspect, the inhalable aerosol comprises about 1 to about 250 mg of aztreonam lysine dissolved in about I to about 5 mL of a saline solution 5 comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In another embodiment of this aspect, the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pm,. In another embodiment of this aspect, a dose of inhalable 10 aerosol is administered three to ten times a day wherein each dose comprises about 1 to about 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 pim. In a preferred embodiment of this 15 aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam. In another preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium 20 chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 pm. In a particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride and 25 delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 jam. In another particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three times a day for at least 28 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, 30 w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pim. 28 WO 2009/045706 PCT/US2008/076431 In another aspect, the invention provides a method of treating the weight symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonam lysine per one 5 dose to the airways of the lung endobronchial space. In another aspect, the invention provides a method of treating the weight symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of a dry powder or inhalable aerosol comprising about 1 to about 250 mg of aztreonam lysine per one 10 dose to the airways of the lung endobronchial space wherein the dose of inhalable dry powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 consecutive days provided that the total daily dose does not exceed 750 mg per day. In one embodiment of this aspect, the inhalable aerosol comprises about I to about 250 mg of aztreonam lysine dissolved in about I to about 5 mL of a saline solution 15 comprising about 0.1 to about 0.45%, w/v, of sodium chloride. In another embodiment of this aspect, the inhalable aerosol is delivered by a nebulizer. In another embodiment of this aspect, the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 ptm. In another embodiment of this aspect, a dose of inhalable 20 aerosol is administered three to ten times a day wherein each dose comprises about I to about 250 mg of aztreonam lysine dissolved in about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pim. In a preferred embodiment of this 25 aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam. In another preferred embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline compri sing about 0.17%, w/v, sodium 30 chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pim. In a particularly preferred embodiment of this aspect, a dose of inhalable aerosol is administered three 29 WO 2009/045706 PCT/US2008/076431 times a day wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 psm. In another particularly preferred 5 embodiment of this aspect, a dose of inhalable aerosol is administered three times a day for at least 28 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 Pin. 10 In another aspect, the invention provides a method of treating one, two, three, four, five, six, seven, eight, nine, ten, eleven or all of the symptom domains of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of an inhalable aerosol of aztreonam lysine three to ten times a day for at least 14 to 28 consecutive days wherein each 15 inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 mun. In one embodiment of this aspect, a dose of inhalable aerosol of aztreonam lysine is administered three to ten times a day 20 for at least 28 consecutive days. In another embodiment of this aspect, the symptom domain of the CFQ-R is the respiratory domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the respiratory domain wherein the domain score is increased by at least 5 points compared to the beginning of the administration. In another embodiment of this aspect, the symptom domain of the 25 CFQ-R is the physical domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the vitality domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the emotional domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the eating domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the treatment 30 burden domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the health perceptions domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the social domain. In another embodiment of this 30 WO 2009/045706 PCT/US2008/076431 aspect, the symptom domain of the CFQ-R is the body image domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the role/school domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the weight domain. In another embodiment of this aspect, the symptom domain of the 5 CFQ-R is the digestion domain. In another aspect, the invention provides a method of treating one, two, three, four, five, six, seven, eight, nine, ten, eleven or all of the symptom domains of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, comprising administering a therapeutically effective amount of an inhalable aerosol of aztreonam 10 lysine three to ten times a day for at least 14 to 28 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and is delivered by electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 im and wherein the patient has a pulmonary Pseudomonas 15 aeruginosa infection. In one embodiment of this aspect, a dose of inhalable aerosol of aztreonam lysine is administered three times a day for at least 28 consecutive days. In another embodiment of this aspect, the symptom domain of the CFQ-R is the respiratory domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the respiratory domain wherein the domain score is increased by at least 20 5 points relative to the beginning of the administration. In another embodiment of this aspect, the symptom domain of the CFQ-R is the physical domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the vitality domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the emotional domain. In another embodiment of this aspect, the symptom domain of the 25 CFQ-R is the eating domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the treatment burden domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the health perceptions domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the social domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is 30 the body image domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the role/school domain. In another embodiment of this aspect, the 31 WO 2009/045706 PCT/US2008/076431 symptom domain of the CFQ-R is the weight domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the digestion domain. Drug Holiday Regimen 5 In one aspect of the invention, the treatments with AZLI are interspersed with courses of treatment with other drugs, particularly antibiotics, or with drug holidays, i.e., wherein no drugs are administered. By way of example and not limitation, the patient would be administered a standard prescribed course of tobramycin inhalation 10 solution for 28 days followed by a 14 to 28 day course of treatment with AZLI. Alternatively, the patient would be administered a 14 to 28 day course of treatment with AZLI followed by a standard prescribed course of tobramycin inhalation solution (28 days). Alternatively, the patient would be administered a 14 to 28 day course of treatment with AZLI followed by a 14 to 28 day drug holiday wherein no drug would 15 be administered. All of these alternating courses of treatment could be recursive. That is, they could be applied one, two, three, four, five, six, seven, eight, nine or more times. In another aspect, the invention provides a method of treating one, two, three, four, five, six, seven, eight, nine, ten, eleven or all of the symptom domains of the CF 20 Questionaire-Revised, in a cystic fibrosis patient in need thereof, wherein the patient has a pulmonary Pseudoionas aeruginosa infection, comprising administering a therapeutically effective amount of an inhalable aerosol aztreonam lysine three to ten times a day for at least 14 to 28 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising 25 about 0.17%, w/v, sodium chloride and is delivered by electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about I to about 5 gin. In one embodiment of this aspect, a dose of inhalable aerosol of aztreonam lysine is administered three to ten times a day for at least 28 consecutive days. In another embodiment of this aspect, a dose of inhalable aerosol of aztreonam lysine is 30 administered three times a day for at least 28 consecutive days. In another embodiment of this aspect, the symptom domain of the CFQ-R is the respiratory domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is 32 WO 2009/045706 PCT/US2008/076431 the respiratory domain and a dose of inhalable aerosol is administered three times a day. In another embodiment of this aspect, the symptom domain of the CFQ-R is the respiratory domain wherein the domain score is increased by at least 5 points relative to the beginning of the inhalable aerosol administration. In another embodiment of 5 this aspect, the symptom domain of the CFQ-R is the respiratory domain wherein the domain score remains increased after a patient's Pseudomonas aeruginosa sputum density has increased to pretreatment concentrations after the cessation of the inhalable aerosol administration. In another embodiment of this aspect, the symptom domain of the CFQ-R is the physical domain. In another embodiment of this aspect, 10 the symptom domain of the CFQ-R is the vitality domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the emotional domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the eating domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the treatment burden domain. In another embodiment of this aspect, the symptom domain 15 of the CFQ-R is the health perceptions domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the social domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the body image domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the role/school domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is 20 the weight domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the digestion domain. In another embodiment of this aspect, the cystic fibrosis patient is previously treated with a prescribed course of tobramycin inhalation solution for 28 consecutive days. In another embodiment of this aspect, the cystic fibrosis patient is treated for 14 to 28 consecutive days with AZLI followed by a 25 standard prescribed course of tobramycin inhalation solution for 28 consecutive days. In another aspect, the invention provides a method of treating one, two, three, four, five, six, seven, eight, nine, ten, eleven or all of the symptom domains of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof, wherein the patient has a pulmonary Pseudomonas aeruginosa infection, comprising a dosing regimen of 30 administering a therapeutically effective amount of an inhalable aerosol of aztreonan lysine three to ten times a day for at least 14 to 28 consecutive days followed by a 14 to 28 consecutive day drug holiday wherein each inhalable aerosol dose comprises 33 WO 2009/045706 PCT/US2008/076431 about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride and is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 tm. In another embodiment of this aspect, the symptom domain of the CFQ-R is the 5 respiratory domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the respiratory domain and a dose of inhalable aerosol is administered three times a day. In another embodiment of this aspect, the symptom domain of the CFQ-R is the respiratory domain wherein the domain score is increased by at least 5 points relative to the beginning of the inhalable aerosol administration. In another 10 embodiment of this aspect, the symptom domain of the CFQ-R is the respiratory domain wherein the domain score remains increased after a patient's Pseudomonas aeruginosa sputum density has increased to at least pretreatment concentrations after the cessation of the inhalable aerosol administration. In another embodiment of this aspect, the symptom domain of the CFQ-R is the physical domain. In another 15 embodiment of this aspect, the symptom domain of the CFQ-R is the vitality domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the emotional domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the eating domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the treatment burden domain. In another embodiment of this 20 aspect, the symptom domain of the CFQ-R is the health perceptions domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the social domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the body image domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the role/school domain. In another embodiment of this aspect, the 25 symptom domain of the CFQ-R is the weight domain. In another embodiment of this aspect, the symptom domain of the CFQ-R is the digestion domain. In another embodiment of this aspect, the dosing regimen is repeated one, two, three, four, five, six, seven, eight or nine times. In another aspect, the invention provides a method of treating the respiratory 30 symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof wherein the patient has a pulmonary Pseudoinonas aeruginosa infection comprising administering a therapeutically effective amount of an inhalable aerosol of 34 WO 2009/045706 PCT/US2008/076431 aztreonam lysine three to ten times a day for at least 14 to 28 consecutive days wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride and is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes 5 comprising MMAD of about 1 to about 5 pn. In another embodiment of this aspect, a dose of inhalable aerosol is administered three to ten times a day for at least 28 consecutive days. In another embodiment of this aspect, a dose of inhalable aerosol is administered three times a day. In another embodiment of this aspect, the respiratory domain score is increased by at least 5 points relative to the beginning of the inhalable 10 aerosol administration. In another embodiment of this aspect, the respiratory domain score remains increased after a patient's Pseudomonas aeruginosa sputum density has increased to at least pretreatment concentrations after the cessation of the inhalable aerosol administration. In another embodiment of this aspect, the cystic fibrosis patient was previously treated with a prescribed course of tobramycin inhalation 15 solution for 28 consecutive days. In another embodiment of this aspect, the cystic fibrosis patient was previously treated with a prescribed course of tobramycin inhalation solution for 28 consecutive days and the respiratory domain score is increased by at least 5 points from the start of the administration of the inhalable aerosol of aztreonam lysine. 20 In another aspect, the invention provides a method of treating the respiratory symptom domain of the CF Questionaire-Revised, in a cystic fibrosis patient in need thereof wherein the patient has a pulmonary Pseudomonas aeruginosa infection, comprising a dosing regimen of administering a therapeutically effective amount of an inhalable aerosol of aztreonam lysine three to ten times a day for at least 14 to 28 25 consecutive days followed by a 14 to 28 consecutive day drug holiday wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride and is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising MMAD of about 1 to about 5 pm. In another embodiment of this aspect, 30 a dose of inhalable aerosol is administered three times a day. In another embodiment of this aspect, the respiratory domain score is increased by at least 5 points after the administration of the inhalable aerosol. In another embodiment of this 35 WO 2009/045706 PCT/US2008/076431 aspect, the respiratory domain score remains increased after a patient's Pseudononas aeruginosa sputum density has increased to at least pretreatment concentrations after the cessation of the inhalable aerosol administration. In another embodiment of this aspect, the dosing regimen is repeated one, two, three, four, five, six, seven, eight or 5 nine times. In another embodiment of this aspect, the dosing regimen is repeated one, two, three, four, five, six, seven, eight or nine times and the respiratory domain score during at least one dosing regimen is increased by at least 5 points compared to the score at the beginning of at least one of the dosing regimens. In another embodiment of this aspect, the dosing regimen is repeated one, two, three, four, five, six, seven, 10 eight or nine times and the respiratory domain score during at least one dosing regimen remains increased after a patient's Pseudomonas aeruginosa sputum density has increased to at least pretreatment concentrations during the drug holiday. In another embodiment of this aspect, the respiratory domain score after an inhalable aerosol administration remains above the respiratory domain score before the 15 inhalable aerosol administration for the entire drug holiday. In another embodiment of this aspect, the inhalable aerosol of aztreonam lysine is administered three times a day for at least 28 consecutive days. Additional Preferred Embodiments 20 1. A method of treating at least one health-related quality-of-life symptom of a lung disease, in a patient in need thereof, comprising administering a therapeutically effective amount of an inhalable dry powder or aerosol comprising about I to about 250 mg of aztreonam lysine per one dose to the airways of the lung.. 25 2. The method of embodiment 2 wherein a dose of inhalable dry powder or aerosol is administered 3 to 10 times a day for at least 14 to 28 consecutive days. 3. The method of embodiment I or 2 wherein the patient has a pulmonary infection caused by griam-negative bacteria. 30 4. The method according to any one of embodiments 1 to 3 wherein the lung disease is cystic fibrosis. 36 WO 2009/045706 PCT/US2008/076431 5. The method of embodiment 4 wherein the health-related quality-of-life symptom is one, two, three, four, five, six, seven, eight, nine, ten, eleven or all of the domains of the Cystic Fibrosis Questionaire-Revised. 5 6. The method of embodiment 5 wherein the domain is selected from the group consisting of the respiratory domain, the body image domain, the digestion domain, the eating domain, the emotional domain, the health perceptions domain, the physical domain, the role/school domain, the social domain, the treatment burden domain, the vitality domain, and the weight domain. 10 7. The method of embodiment 6 wherein the respiratory domain score is increased by at least 5 points compared to the score immediately before the administration of the inhalable aerosol. 15 8. The method of any one of embodiments I to 7 wherein the inhalable aerosol comprises about 1 to about 250 mg of aztreonam lysine per one dose dissolved in about 1 to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride. 20 9. The method of any one of embodiments 1 to 8 wherein the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising mass median aerodynamic diameters of about 1 to about 5 ptm. 10. The method of any one of embodiments 1 to 9 wherein the dose of inhalable 25 aerosol is administered three times a day. 11. The method of any one of embodiments 6 to 10 wherein the respiratory domain score is increased by at least 5 points compared to the score immediately before the administration of the inhalable aerosol. 30 37 WO 2009/045706 PCT/US2008/076431 12. The method of any one of embodiments I to 11 wherein each dose of inhalable aerosol comprises about 75 mg of aztreonam dissolved in about 1 mL of saline comprising about 0.17%, w/v, sodium chloride. 5 13. The method of any one of embodiments 6 to 12 wherein the respiratory domain score is increased by at least 5 points compared to the score immediately before the administration of the inhalable aerosol. 14. The method of any one of embodiments 1 to 13 wherein the patient has a 10 pulmonary Pseudomonas aeruginosa infection. 15. The method of any one of embodiments 1 to 14 wherein the administration of the inhalable aerosol is preceded by a standard prescribed 28 day administration of tobramycin inhalation solution. 15 16. The method of any one of embodiments of 6 to 15 wherein the respiratory domain score is increased by at least 5 points compared to the score immediately before the administration of the inhalable aerosol of aztreonam lysine. 20 17. The method of any one of embodiments 6 to 16 wherein the respiratory domain score is increased by at least 5 points compared to the score immediately before the administration of the inhalable aerosol. 18. The method of any one of embodiments 6 to 17 wherein the respiratory 25 domain score remains increased after a patient's Pseudomonas aeruginosa sputum density has increased to at least pretreatment concentrations after the cessation of the inhalable aerosol administration. 19. The method of any one of embodiments 2 to 18 wherein at least one 14 to 28 30 consecutive day inhalable aerosol administration is followed by a 14 to 28 day drug holiday. 38 WO 2009/045706 PCT/US2008/076431 20. The method of any one of embodiments 2 to 19 wherein the at least one 14 to 28 consecutive day inhalable aerosol administration followed by a 14 to 28 consecutive day drug holiday defines a dosing regimen that is repeated one to nine times. 5 21. The method of any one of embodiments 2 to 20 wherein, during at least one regimen, the respiratory domain score following the 14 to 28 consecutive day inhalable aerosol administration is increased by at least 5 points compared to the score immediately before the 14 to 28 consecutive day inhalable aerosol administration. 10 22. The method of any one of embodiments 2 to 21 wherein, during at least one dosing regimen, the respiratory domain score following the 14 to 28 day inhalable aerosol administration remains increased compared to the score immediately before the 14 to 28 consecutive day inhalable aerosol administration after a patient's 15 Pseudomonas aeruginosa sputum density during the drug holiday has increased to at least the concentration at the beginning of the dosing regimen. 23. The method of any one of embodiments 2 to 22 wherein the regimen is repeated at least three times and the respiratory domain score remains increased 20 compared to the score immediately before the first regimen. Aztreonam lysine for inhalation (AZLI) As used herein, unless otherwise indicated, aztreonam lysine and aztreonam 25 lysinate are synonymous. Aztreonam lysine for inhalation is a white to off-white powder formed by combining alpha-aztreonam with L-lysine (Montgomery, US patents 6660249, 7,138,419, 7208,141, 7,214,364, US patent applications 11/732,234 and 11/729,698; each of which is incorporated by reference herein in their entirety). The resulting product is a 1.9:1 molar ratio of L-lysine monohydrate to aztreonam. 30 Therefore, by way of example and not limitation, in a preferred single dosage form, the aztreonam lysine for inhalation comprises 75 mg of aztreonam and 52.5 mg of L lysine monohydrate (46.7 mg of L-lysine). 39 WO 2009/045706 PCT/US2008/076431 AZLI is suitable for efficacious delivery to the airways of the lung endobronchial space by aerosolization or as a dry powder. Most preferably, AZLI is suitable for formulation as a concentrated aztreonam lysine for aerosolization by atomizing, jet, ultrasonic, pressurized, vibrating porous plate or equivalent nebulizers 5 or by dry powder inhalers which predominantly produce aztreonam lysine aerosol or dry powder particles comprising MMAD of about 1 to about 5 jim. The AZLI may be endobronchially administered in a dry powder that has been fonnulated for efficacious delivery of the finely milled AZLI powder into the endobronchial space using a dry powder or metered dose inhaler. For delivery of a 10 dry powder, the AZLI in the formulation is milled, precipitated, spray dried or otherwise processed to particle sizes comprising predominantly MMAD of about 1 to about 5 pim. AZLI compositions for aerosolization are formulated for efficacious delivery of aerosolized aztreonam lysine to the airways of the lung endobronchial space. The 15 aerosol formulation is delivered in a total volume of between about 1 and about 5 mL of aqueous physiologically acceptable solution for one inhalation dose. When formulated and delivered according to the method of invention, it delivers a therapeutically efficacious dose of aztreonam lysine to the airways of the lung endobronchial space to treat the health-related quality-of-life symptoms of cystic 20 fibrosis, in a patient in need thereof. The aerosolizable formulations contain a minimal yet efficacious amount of aztreonam lysine from about I to about 250 mg, more preferably from about 25 to about 150 mg/mL, and most preferably about 122 mg/mL; formulated in the smallest possible volume of physiologically acceptable diluent having a certain degree of 25 salinity and a certain pH. range. The concentration of aztreonam lysine, salinity, and pH range is adjusted to permit generation of an aztreonam lysine aerosol that is well tolerated by patients and that minimizes the development of undesirable side effects such as bronchospasm and cough. In a non-limiting, preferred single dose formulation, AZLI is dissolved in 30 about 1 mL of about 0.17% sodium chloride, w/v, just prior to administration by aerosolization. 40 WO 2009/045706 PCT/US2008/076431 A combination of the aqueous fonnulations of AZLI with the atomizing, jet, pressurized, vibrating porous plate, ultrasonic, or electronic nebulizer permits, depending on the nebulizer, about at least 20 to about 90%, most typically 70%, delivery of the administered dose of aztreonam lysine into the airways of the lung. 5 Devices for Delivery of AZLI Nebulizers Compositions of the invention described above provide the AZLI formulated 10 in a solution permitting delivery of a therapeutically effective amount of aztreonam lysine provided that the aerosol generated by nebulization meets criteria required for efficient delivery of the drug. Therefore, the nebulizer which aerosolizes the formulation of AZLI becomes an important feature of the invention. Although many nebulizer types are commercially available, not all are suitable for practicing the 15 instant invention. A nebulizer is selected primarily on the basis of its ability to aerosolize the aqueous AZLI formulation into particles comprising a MMAD predominantly between about 1 and about 5 tm. Jet, ultrasonic, and atomizing nebulizers have been developed that produce aerosol particles with the required predominant MMAD. 20 The nebulizer must also be efficient in generating the aerosol of required particle sizes from a concentrated small volume of fonnulation to limit drug cost and time required to administer an efficacious dose. A combination of an aqueous AZLI formulation and a nebulizing device significantly enhances the efficiency and speed of aztreonam lysine administration. For example, the average time for administration 25 of other aerosolized drugs such as tobramycin is 15 -20 munutes per dose. The time required for this treatment represents a significant burden to the patient and contributes to reduced compliance with the prescribed twice a day regimen. Furthermore, the nebulizer system used for tobramycin administration is less efficient than new atomizing devices, The total dose of tobramycin deposited in the lung is in 30 the 12 to 15% range; approximately 30% of the dispensed drug remains in the nebulizer at the end of treatment; and, of the portion of drug aerosolized, about 30% is emitted as particles too large or small to reach the lower airways. 41 WO 2009/045706 PCT/US2008/076431 Typical nebulizing devices suitable for practicing the instant invention include atomizing nebulizers, modified jet nebulizers, ultrasonic nebulizers, and electronic nebulizers modified for handling small volumes of highly concentrated drug in a specific formulation having a specific pH, osmolality and salinity. 5 A particularly preferred nebulizer is the Pari eFlowR Electronic Nebulizer as disclosed in US patents 5,152,456, 5,261,601, 5,518,179, 6,983,747, 6,962,151, and International Application WOO1/034232; each of which is incorporated by reference herein in their entirety. This atomizing nebulizer, with an output of 8 to 10 jiL/second, or 0.48 to 0.60 mL/minutes, is capable of delivering drug material 2 to 4 10 times faster than earlier nebulizers such as the PARI LC plus NebulizerR. Furthermore, this nebulizer is able to aerosolize approximately 90% of the dispensed dose, with 85% or more of the aerosol particles being with the size range required for lower airway deposition. Administration of a specifically designed formulation of AZLI, such as those described herein, using the eFlow Nebulizer leads to a substantial 15 improvement in lower airway delivery and to treatment times as short as three or four minutes. Dry Powder Inhalers 20 There are two major designs for dry powder inhalers. One design is the metering device in which a reservoir for the drug is placed within the device and the patient adds a dose of the drug into the inhalation chamber. The second is a factory metered device in which each individual dose has been manufactured in a separate container. Both systems depend upon the formulation of the drug into small particles 25 with MMAD from about 1 to about 5 pm, and usually involve co-formulation with larger excipient particles such as 100 jim diameter lactose particles. Drug powder is placed into the inhalation chamber (either by device metering or by breakage of a factory-metered dosage) and the inspiratory flow of the patient accelerates the powder out of the device and into the oral cavity. Non-laminar flow characteristics of the 30 powder path cause the excipient-drug aggregates to decompose, and the mass of the large excipient particles causes their impaction at the back of the throat, while the smaller drug particles are deposited deep in the lungs. 42 WO 2009/045706 PCT/US2008/076431 Current technology for dry powder inhalers is such that payload limits are around 100 mg of powder. Therefore multiple activations of the dry powder inhalers and subsequent patient inspirations may be required to provide efficacious doses of astreonam lysine with these devices. 5 Definitions Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings: 10 When trade names are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) or device of the tradename product. The term "aerosol", as used herein, unless otherwise indicated, means a suspension of fine liquid or solid particles or combinations thereof in a gas. As used 15 herein, the term shall also incorporate the formulation that is used in generating the aerosol. The term "inhalable aerosol", as used herein, unless otherwise indicated, means an aerosol as defined above that is adapted to be physiologically acceptable. Important non-limiting aspects in making an inhalable aerosol physiologically 20 acceptable include pH, osmolality, and permeable anion concentration. As used herein, the term shall also incorporate the formulation that is used in generating the inhalable aerosol. The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or 25 condition to which such term applies, or one or more symptoms of such disorder or condition. A non-limiting example of "treating" is to increase the score of one or more domains of an HRQOL instrument. The term "treatment", as used herein, refers to the act of treating, as "treating" is defined immediately above. The term "therapeutically effective amount", as used herein, is the amount of 30 aztreonarn lysine present in a composition described herein, such as an inhalable aerosol, that is needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated 43 WO 2009/045706 PCT/US2008/076431 to give an anticipated physiological response, desired biological effect, or improvement in a domain of a HR QOL instrument when such a composition is administered by inhalation. The precise amount will depend upon numerous factors, for example the particular formulation, the specific activity of the composition, the 5 delivery device employed, the physical characteristics of the composition, its intended use, as well as patient considerations such as severity of the disease state, patient cooperation, etc., and can readily be determined by one skilled in the art based upon the information provided herein. The term "MMAD" means mass median aerodynamic diameter. 10 The term "predominantly" or "predominant" when referring to particle size, means including at least 70% but preferably 90% of particle sizes between 1 vm and 5 The term "w/v" means weight to volume. The modifier "about" used in connection with a quantity is inclusive of the 15 stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity). The term "prescribed course(s)" means the course of treatment indicated on the label or package insert of a registered drug. The term "CFQ-R" or "CF-Questionaire-Revised" means the HRQRL 20 instrument Cystic Fibrosis Questionaire-Revised. The term "TIS" means tobramycin inhalation solution, USP or TOB1R. The term "drug holiday" means that a patient stops taking a medication for a period of time. The term "Pseudomonas aeruginosa sputum density" or "PA sputum density" 25 means the concentration of Pseudomonas aeruginosa in the sputum of a patient as determined by the number of colony forming units (CFU) in a standardized microbiological culture for Pseudomonas aeruginosa. Examples 30 INTRODUCTION: Clinical Trial I. 44 WO 2009/045706 PCT/US2008/076431 The study described herein included patients with CF who frequently utilized antibiotics for PA airway infections, assessing the effectiveness of AZLI in this intensively-treated patient population. Early treatment of pulmonary exacerbations has resulted in fewer hospitalizations; thus time to hospitalization has become less 5 clinically relevant as a study endpoint. Therefore, clinical deterioration was assessed with a new measure: time to need for additional antipseudomonal antibiotics to treat symptoms indicative of pulmonary exacerbation (Rosenfeld, M, J. Pediatr 2001; 139:359-65). Patient-reported improvements in clinical symptoms were measured with the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a validated health-related 10 quality-of-life measure. An established efficacy measure, change in FEVI, was also included in the study. This combination of endpoints provided a broad view of patient responses to AZLI therapy. The clinical study described later under Clinical Trial II assessed the safety and efficacy of AZLI to treat PA airway infection in patients with CF who infrequently utilized antipseudomonal-maintenance therapy. 15 METHODS Study Design This randomized, double-blind, placebo-controlled, study was conducted at 56 US CF centers (February, 2005-September, 2006). After screening (Day -42, 20 Figure 1), eligible patients were enrolled (Day -28), randomly assigned to 75 mg AZLI (twice [BID] or three times [TID] daily) or placebo (1:1:1), and began treatment with open-label TIS (Day -28). At baseline (Day 0), patients completed the course of TIS and began the randomized AZLI/placebo treatment. Patients were monitored mid-treatment (Day 14), at end of treatment (Day 28), and during followup 25 (Days 42, 56, 70, 84). A complete physical examination was performed at screening. Spirometry (American Thoracic Society standards) was performed at every study visit (before and 30 minutes after any treatment) (Am J Respir Crit Care Med 1995;152:1107-36). FEV % predicted values were calculated using the Knudson equation (Knudson, RJ, 30 Am Rev Respir Dis 1983;127:725-34). TIS (300 mg, BID) was administered with the PARI LC* PLUS jet nebulizer and AZLI (75 mg aztreonam, 52.5 mg lysine monohydrate) or placebo (5 mg lactose), 45 WO 2009/045706 PCT/US2008/076431 diluted in 1 mL of 0.17% NaCl (BID or TID), with the eFlow* Electronic Nebulizer (PARI Innovative Manufacturers, Midlothian, VA). Patients self-administered a bronchodilator at home before study medication and a short-acting p2-agonist 15 minutes before the first spirometry measurements at study visits. Patients continued 5 any prescribed bronchodilator use, excluding the 6 hours before study visits. TIS was dispensed on Day -28 and AZLI/placebo on Day 0; used and unused vials were subsequently collected to assess treatment compliance. This study was conducted in compliance with the Declaration of Helsinki. Institutional Review Boards approved the study for each site and all patients or their 10 guardians provided written informed consent prior to any study procedures. The ClinicalTrials.gov accession number is NCTO0 104520. Study Population Eligible patients ( 6 years, documented diagnosis of CF) had current PA 15 airway infections, >3 TIS courses within the previous year, the ability to perform reproducible pulmonary function tests, and, at screening, FEV, 25% and 575% predicted values and arterial oxygen saturation 90% on room air. Chronic azithromycin use was allowed if the regimen was unchanged in the previous 3 months and if additional antipseudomonal therapy had been utilized since initiating 20 azithromycin. Exclusion criteria included current oral corticosteroid use (equivalent to >10 mg prednisone daily); airway cultures yielding Burkholderia cepacia complex in previous 2 years; oxygen supplementation: daily continuous or >2 L/minute at night; monobactam-antibiotic hypersensitivity; inhaled short-acting p2-agonist intolerance; 25 recent changes in antimicrobial, bronchodilator, anti-inflammatory, corticosteroid medications or physiotherapy technique/schedule; lung transplantation; new finding on chest radiograph at screening; AST or ALT > 5-times or serum creatinine >2-times upper limit of normal (at screening); pregnancy; lactation; or, in opinion of investigator, medical or psychiatric illness interfering with study participation. 30 Efficacy Measures 46 WO 2009/045706 PCT/US2008/076431 The primary efficacy endpoint was time to need for additional inhaled or IV antipseudomonal antibiotics to treat symptoms indicative of pulmonary exacerbation. The predefined list of symptoms included decreased exercise tolerance, increased cough, increased sputum production/chest congestion, or decreased appetite. Major 5 secondary efficacy endpoints included changes in clinical symptoms (CFQ-R Respiratory Symptoms Scale), pulmonary function, PA density (colony forming units (CFU)/gram sputum, logio transformed), time to hospitalization, hospitalizations, and weight. Scores for CFQ-R Scales ranged from 0 to 100; increasing scores indicated improvement. The CFQ-R was administered at the beginning of study visits to 10 minimize any influence of physiological data or study personnel on patient responses. Using responses during the TIS phase to a Global Rating of Change Questionnaire (GRCQ)-Respiratory Domain, a minimal clinically important difference (MCID) score of 5 was determined for the CFQ-R-Respiratory Scale; thus 5 point changes indicated improving/worsening respiratory symptoms (Guyatt, GH, Med Care 15 2000:11:175-9; Jaeschke, R, Control Clin Trials 1989;10:407-15). Microbiological endpoints included the minimum inhibitory concentration (MIC) of aztreonam for PA, and the prevalence of other pathogens. Safety Measures 20 Safety was assessed by monitoring adverse events and changes in clinical laboratory values, vital signs, and airway reactivity. Worsening CF symptoms were treated as adverse events and patients were withdrawn from the study if they exhibited any of the predefined symptoms of pulmonary exacerbation (Rosenfeld, M, J Pediatr 2001;139:359-65). Patients who withdrew for the combination of predefined 25 symptoms and need for additional antibiotics met the primary efficacy endpoint; completing their study participation. Statistical Analyses Efficacy and safety analyses included all randomly-assigned patients receiving 30 1 dose of AZLI/placebo. As specified in the study protocol, responses of placebo BID and placebo-TID groups were pooled. A sample size of 210 patients for 47 WO 2009/045706 PCT/US2008/076431 AZLI/placebo treatment was estimated as providing >90% power to detect a difference in time to antibiotic need, with a=0.05. CFQ-R and FEV efficacy analyses used the last observation carried forward convention. Analyses of continuous variables used Analysis of Covariance 5 (ANCOVA) models with treatment as the fixed effect and baseline (Day 0) values as covariates. The highest aztreonam MIC at baseline was the covariant for analyzing logo PA CFUs. Changes in FEVI (liters) and changes in FEV 1 % predicted were analyzed using relative values; increases or decreases were calculated as percentages of the baseline FEV 1 or FEV % predicted values. Time to antibiotic need and to 10 hospitalization were analyzed using Kaplan-Meier estimates and treatment groups compared using the log-rank test. Hospitalizations were analyzed using Wilcoxon rank-sum test (days) and Fisher's Exact test (proportion of patients). Aztreonam concentrations (Alta Analytical Laboratory, El Dorado Hills, CA) in plasma and sputum were summarized, as were aztreonam or tobramycin MIC values inhibiting 15 50% (MIC 5 o) or 90% (MIC 90 ) of PA isolates, proportion of patients with aztreonam or tobramycin MIC values above parenteral breakpoints, and the prevalence of other pathogenic bacteria (Covance Central Laboratory Services, Indianapolis, IN) (Gibson, RL, Am J Respir Crit Care Med 2003;168:918-51; Gibson, RL, Pediatr Pulmonol 2006;41:656-65; Burns JL, Clin Infect Dis 1998;27:158-63). Statistical 20 Analysis Software versions 8.02 and 9.1 were used (SAS®, SAS Institute Inc, Cary, NC). RESULTS Of 363 patients screened, 211 completed the 28-day TIS run-in and began the 25 28-day AZLI/placebo treatment; 173 (82%) completed treatment (Figure 1). Compliance was 99.5% during TIS run-in ( 50% doses) and 95.3% during AZLI/placebo treatment ( 66% doses). Worsening respiratory symptoms prompted most discontinuations during AZLI/placebo treatment. The majority of discontinuing patients (Days 0-84) also met the primary study endpoint, need for IV or inhaled 30 antipseudomonal antibiotics (AZLI-BID: 17 of 32 withdrawing; AZLI-TID: 21 of 39; placebo: 38 of 50; Figures 1, 2). 48 WO 2009/045706 PCT/US2008/076431 Patient Characteristics Patient characteristics appeared well balanced between treatment groups (Table 3). Mean age was 26.2 years, with 165 (78%) patients 18-years of age. Mean FEV 1 % predicted was 55.1%; FEVI was 50% predicted value for 76 (36%) 5 patients. Concomitant medications used at screening (>50% patients) were pancreatic enzymes (92%), salbutamol (89%), dornase alfa (85%), vitamins (84 %), azithromycin (70%), and fluticasone propionate with salmeterol (56%). Average TIS use was 5.3 courses in the year before the study; 6.5 courses/year is the maximum number approved (Prescribing information, TOBI®, tobramycin inhalation solution, 10 USP). Efficacy Less than half the AZLI-treated patients had required additional inhaled or IV antipseudomonal antibiotics by study end (Day 84); thus the median time to antibiotic 15 need was greater than 84 days (Figure 2). Data were available on use of antipseudomonal antibiotics to treat predefined respiratory symptoms occurring during the 2 weeks after study end/early withdrawal. By including these data (16 patients, added before unblinding the study), we determined the median time to antibiotic need was 21 days longer for the AZLI-pooled group than for the placebo 20 group (92 vs 71 days, measured from baseline; P=0.007; Figure 2). Median time to antibiotic need was also longer in the AZLI-BID (>92 days, P=0.002) and AZLI-TID (87 days, P=0.182) groups, compared with placebo (71 days). Adjusted mean CFQ-R-Respiratory scores increased 5.01 points in the AZLI-pooled group compared with placebo (Day 28, 95% confidence interval [CI]: 25 0.81, 9.21; P=0.020). Significant improvements were observed for both AZLI-BID and AZLI-TID groups compared with placebo (Figure 3). Scores decreased during the followup period (Day 84; AZLI-pooled: 0.71 points; placebo: -0.78 points; change from Day 0). During AZLI/placebo treatment (Days 0-28), CFQ-R-Respiratory scores improved for more AZLI-treated than placebo-treated patients ( 5 point 30 increase; AZLI: 52%; placebo: 37%) and worsened for fewer AZLI-treated patients ( 5 point decrease; AZLI: 28%; placebo: 38%; overall categorical comparison, P=0.029). 49 WO 2009/045706 PCT/US2008/076431 Adjusted mean FEVI improved 6.3% in the AZLI-pooled group compared with placebo (Day 28, 95% Cl: 2.5, 10.1; P=0.00l). Significant improvements were. observed for both AZLI-BID and AZLI-TID groups compared with placebo (Figure 3). FEV decreased during the followup period for all groups. During both TIS run 5 in and AZLI treatment, improvement in observed FEV 1 was larger for the AZLI-TID than for the AZLI-BID group; this larger improvement was followed by a larger decline for the AZLI-TID group during the followup period (Figure 4). Adjusted mean FEV2 % predicted also improved in the AZLI-pooled group compared with placebo (Day 28, treatment effect =6.6%; 95% Cl: 2.8, 10.4; 10 P<0.001). Changes in CFQ-R-Respiratory scores at end of treatment (Day 28) were modestly correlated with changes in FEVI (Pearson correlation coefficients =0.33, 0.24, 0.33; AZLI-BID, AZLI-TID, placebo; Figure 5) and with GRCQ-Respiratory Domain responses (Pearson correlation coefficient =0.46, all groups combined, 15 P<0.001). Adjusted mean PA sputum density decreased 0.66 logo PA CFU/gram sputum in the AZLI-pooled group compared with the placebo group (Day 28, 95% CI: -1.13, -0.19; P =0.006). Significant decreases were observed for both AZLI-BID and AZLI-TID compared with placebo (Figure 3). PA density increased for all groups 20 during the followup period. During the 28-day TIS run-in, mean CFQ-R-Respiratory scores decreased 1.47, mean FEV 1 increased 0.9%, and mean PA density decreased 0.28 logio PA CFU/gram sputum. Time to first hospitalization and median days/number patients hospitalized did 25 not differ significantly between treatment groups (Days 0-84). Weight increased 0.77% for the AZLI-pooled group compared with placebo (Day 28, 95% CI: 0.00, 1.55; P=0.051). Safety 30 The incidence of treatment-emergent adverse events was generally comparable for the three groups (Table 4); any differences were not statistically significant. Nine patients were hospitalized because of serious adverse events occurring during the 50 WO 2009/045706 PCT/US2008/076431 AZLI/placebo treatment period; seven for pulmonary exacerbation (AZLI-BID: 2; AZLI-TID: 4; placebo: 1) and one each for small bowel obstruction (AZLI-BID) and hyponatremia (AZLI-TID). There were no deaths during this study and no reports of anaphylaxis. Airway reactivity after treatment (acute FEVI decrease 15% within 5 30 minutes post-treatment; Days 0, 14) occurred in 6 patients (AZLI-pooled: 4 [3.0%]; placebo: 2 [2.6%]); none of these patients withdrew for this reason. Mean changes in vital signs and in hematology and serun chemistry variables from Day -28 or Day 0 were comparable for all treatment groups during the study. Mean total white blood cell counts, neutrophil counts, % neutrophils, and serum 10 glucose concentrations were near or above the upper limit of normal for all treatment groups throughout the study. Clinical Pharmacology and Microbiology On Day 14, aztreonam concentrations in plasma 1 hour postdose were (median 15 [range]): AZLI-BID: 581 (45-1540) ng/mL and AZLI-TID: 622 (31-1710) ng/mL and in sputum 10 minutes postdose were: AZLI-BID: 429 (0.273-3430) tg/gram and AZLI-TID: 406 (68-3240) jig/gram.

MIC

5 and MIC 90 values of aztreonam for PA remained unchanged between Days 0 and 56 except for a transient 4-fold increase on Day 14 in the AZLI-TID 20 group. The proportion of patients having PA isolates with aztreonam MIC values >8 [pg/mL (parenteral breakpoint) increased during AZLI treatment; the increase was transient in the AZLI-TID group (Day 0, 28, 42, AZLI-BID: 27%, 44%, 39%; AZLI TID: 33%, 43%, 28%; placebo: 38%, 37%, 30%) (Gibson, RL, Am J. Respir Crit Care Med 2003; 168:918-51). MIC 50 and MIC 9 0 values of tobramycin for PA isolates 25 changed 4-fold (Days -28 to 56). The proportion of patients having PA with tobramycin MIC values 8 tg/mL (parenteral breakpoint) did not increase (Days -28 to 42). No persistent increases were observed for the prevalence of Staphylococcus aureus, Stenotrophomonas maltophilia, or Achromobacter xylosoxidans (Days 0-28); B. cepacia complex was not isolated. 30 51 WO 2009/045706 PCT/US2008/076431 DISCUSSION Inhalation of aztreonam lysine (AZLI) at a dose of 75 mg, BID or TID for 28 days, significantly delayed time to need for additional inhaled or IV antipseudomonal antibiotics to treat respiratory symptoms indicative of pulmonary 5 exacerbation in patients with CF. Compared with placebo, AZLI treatment also significantly improved respiratory symptoms and pulmonary function and significantly decreased logio PA CFUs. AZLI was well tolerated; adverse events were generally consistent with the symptoms of CF lung disease. Although the study entry criteria were comparable, patients in this study were 10 older (26 vs. 21 years) with higher mean FEVI % predicted (55% vs. 50-51%) than patients in TIS studies a decade ago (Ramsey, BW, N. Engl. J. Med. 1999; 341:23 30). This patient population, despite being older, had less lung-disease progression; likely reflecting the improved clinical management of CF. Patient responses during the TIS run-in period appeared markedly attenuated 15 compared with responses observed in previous TIS studies (Ramsey, BW, N. Engl. J. Med. 1999; 341:23-30; JMoss, RB, Chest 2001; 120(Suppl):107-13S; Moss, RB, Chest 2002; 121:55-63; Ramsey, BS, N. Engl. J. Med. 1993; 328:1740-46; Smith AL, Pediatr. Pulmonol. 1989; 7:265-71; Hodson, ME, Eur Respir J. 2002; 20:658-64). Further studies will be required to elucidate the mechanism(s) underlying this 20 apparent attenuation in clinical efficacy resulting from chronic TIS use. An increase in FEV 1 was observed after 28 days of AZLI treatment, therefore AZLI appears to circumvent the mechanism(s) affecting patient responses to TIS. However, this study included only one treatment period and the effectiveness of AZLI and the development of microbial resistance need to be examined over longer time periods 25 and multiple treatment courses. The increased CFQ-R-Respiratory scores indicated that patients perceived their respiratory symptoms as improving following AZLI treatment. CFQ-R-Respiratory scores appeared to detect change in this CF population with sensitivity equal to FEVI, the established efficacy endpoint. However, these 30 endpoints are measuring different aspects of clinical efficacy, as indicated by the modest correlation between patient-reported changes in respiratory symptoms (CFQ 52 WO 2009/045706 PCT/US2008/076431 R-Respiratory) and measured changes in lung function (FEV 1 ) (Goss, CH, Proc. Amer. Thorac. Soc. 2007; 4:378-86). Patients in this study were predominantly adults (78% 18 years) and were extensively treated. In addition to the TIS run-in, TIS use in the previous year 5 averaged 5.3 courses, approaching the maximum of 6.5 courses per year approved. Thus, the magnitude of improvement in FEVI (6.3%) and FEVI % predicted (6.6%) following AZLI treatment was unexpected, and suggests that lung disease in adults with CF may be more responsive to additional treatment than previously believed. Observed FEV1 improved more for patients randomly assigned to the AZLI 10 TID group than to the AZLI-BID or placebo groups during both the TIS run-in and the AZLI/placebo treatment periods; a correspondingly larger decrease occurred during followup. Patients in the AZLI-TID group may have perceived this decrease as worsening respiratory symptoms and this may have accounted for the shorter time to antibiotic need observed for the AZLI-TID group. 15 The decrease in PA sputum density after AZLI treatment was small but statistically significant and was observed in clinically stable patients immediately after a course of TIS. The decrease was comparable to those observed in previous TIS studies enrolling intensively-treated patients, but smaller than those observed in previous AZLI studies enrolling less intensively-treated patients (see Clinical Trial II; 20 Hodson, ME, Eur. Respir. J. 2002; 20:658-64; Lamb, HM, Dis. Manage. Health Outcomes 1999; 6:93-108). Thus for PA density, the magnitude of change appears dependent on recent antibiotic therapies. The results of this study indicate that AZLI may be an effective "add-on" therapy for patients with CF and chronic PA airway infection who are intensively 25 treated with TIS; in 2005, this group included 58% of US patients (>5 years of age) with CF and PA airway infection. The improvements in FEV I and PA sputum density decreased during the two weeks after therapy stopped. Thus, to maintain lung function, future strategies for managing patients may include rotating use of different inhaled antibiotics or use of combination therapies. 53 WO 2009/045706 PCT/US2008/076431 ~Ln N? mN NN CO orn COV e -- Nv A u r\ r\ r- N CO .0N O)D r~~rL CN 1%0~ - 0 0 -D0\ 0 0 N N n m n M \-I-iC r) /TtNr -) II ' - Qr-- - ;L . c'Jne 0" (D n* T u~ U 0 P4 tntnoyu CC - t0N0~Th N4-eEl >Nr~en~e.~c'cY ncn~e54 WO 2009/045706 PCT/US2008/076431 Table 4. Treatment-Emergent Adverse Events (TEAEs) 5.0 % in any Treatment Group during the ALZI/placebo Treatment Period. TEAEs 5 % in any Placebo AZLI-BID AZLI-TID AZLI-Pooled treatment group*, n (%) n=76 n=69 n=66 n=135 Cough 26 (34.2) 19 (27.5) 24 (36.4) 43 (31.9) Productive Cough 13(17.1) 9 (13.0) 9 (13.6) 18 (13.3) Wheezing 6 (7.9) 5 (7.2) 9 (13.6) 14 (10.4) Haemoptysis 7 (9.2) 7 (10.1) 6 (9.1) 13 (9.6) Nasal Congestion 6 (7.9) 5 (7.2) 5 (7.6) 10 (7.4) Rhinorrhoea 2 (2.6) 5 (7.2) 5 (7.6) 10 (7.4) Headache 5 (6.6) 2 (2.9) 6 (9.1) 8 (5.9) Pharyngolaryngeal Pain 7 (9.2) 3 (4.3) 5 (7.6) 8 (5.9) Dyspnoea 3 (3.9) 2 (2.9) 5 (7.6) 7 (5.2) Pyrexia 2 (2.6) 4 (5.8) 3 (4.5) 7 (5.2) Respiratory Tract Congestion 5 (6.6) 5 (7.2) 2 (3.0) 7 (5.2) Abdominal Pain, Upper 3 (3.9) 4 (5.8) 1 (1.5) 5 (3.7) Decreased Appetite 5 (6.6) 4 (5.8) 1 (1.5) 5 (3.7) Fatigue 7 (9.2) 3 (4.3) 2 (3.0) 5 (3.7) Dysphonia 4 (5.3) 1 (1.4) 1 (1.5) 2 (1.5) Exercise Tolerance Decreased 4 (5.3) 1 (1.4) 1 (1.5) 2 (1.5) Sinus Congestion 5 (5.6) 0 (0.0) 2 (3.0) 2 (1.5) *TEAEs coded using the Medical Dictionary for Regulatory Activities (MedDRA) preferred term; for TEAEs with incidence 10% in any group, % patients for each TEAE 5 did not differ significantly between treatment groups (Fisher's Exact test). Clinical Trial II The study described herein assessed the efficacy and safety of AZLI 75 mg, administered three times daily for 28 days to patients with moderate to severe CF lung 10 disease and PA airway infection. The primary efficacy endpoint was change in clinical symptoms, measured with the CF Questionnaire-Revised Respiratory Scale (CFQ-R-Respiratory). This study focused on patients with CF who had not been intensively treated with TIS during the previous year and were not being treated with azithromycin at study entry. 15 METHODS Study Design This randomized, double-blind, placebo-controlled, study was conducted at 53 CF centers in the US, Canada, Australia, and New Zealand (June, 2005-April, 2007). At 20 baseline (Day 0), eligible patients were stratified by CF disease severity using 55 WO 2009/045706 PCT/US2008/076431 FEVI % predicted (moderate: FEVI >50% to 75% predicted; severe: FEVi 25% to 50% predicted; measured at screening {between Days -14 and -7]), and randomly assigned to 28-days treatment with 75 mg AZLI or placebo (1:1; three times daily). Patients were monitored mid-treatment (Day 14), at treatment end (Day 28), and 14 days 5 after completing treatment (Day 42; Figure 6). A physical exam was performed at screening. Spirometry (American Thoracic Society standards, Am J. Respir. Crit. Care Med. 1995; 152:1107-36) was performed at every study visit (before and 30 minutes after any treatment). FEV 1 % predicted values were calculated using the Knudson equation. 10 AZLI (75 mg aztreonam, 52.5 mg lysine monohydrate) or placebo (5 mg lactose), diluted in 1 mL 0.17% NaCl, were administered with the eFlow* Electronic Nebulizer (PARI Innovative Manufacturers, Midlothian, VA). Patients self-administered a short-acting p2-agonist 15 minutes before the first spirometry measurements at study visits and self-administered a p2-agonist before study medication at home (within 2 hours 15 before dosing for short-acting or 30 minutes to 8 hours before dosing for long-acting agents). Patients continued any prescribed bronchodilator use, excluding a 4 hour period before study visits. Study medication was dispensed at baseline; used/unused vials were subsequently collected to assess treatment compliance. 20 This study was conducted in compliance with the Declaration of Helsinki, the International Conference on Harmonisation guideline for Good Clinical Practices, and the applicable regulations for each participating country. Institutional Review Boards (U.S.) and Ethics Committees (Canada, Australia, New Zealand) approved the study for each site, and all patients or their guardians provided written informed consent prior to any 25 study procedures. The ClinicalTrials.gov accession number is NCTOOI 12359. Study Population Eligible patients were 6 years of age with a documented diagnosis of CF and moderate to severe lung disease (FEVI 225% to 75% predicted), arterial oxygen 30 saturation 90% on room air (at screening), the ability to perform reproducible 56 WO 2009/045706 PCT/US2008/076431 pulmonary function tests, and PA airway infection (documented at screening or twice within previous year, including once within previous 3 months). Exclusion criteria included recent (Day -28 to screening) inhaled, intravenous, or oral administration of antipseudornonal antibiotics or azithromycin; recent aerosolized 5 hypertonic saline use (except for sputum induction); current oral corticosteroid use equivalent to >10 mg prednisone daily; airway cultures yielding Burkholderia cepacia complex during previous 2 years; daily continuous oxygen supplementation or >2 L/minute at night; local or systemic hypersensitivity to monobactam antibiotics; intolerance to inhaled short-acting p2-agonists; recent (since 7 days before screening) 10 changes in antimicrobial, bronchodilator, anti-inflammatory, corticosteroid medications or physiotherapy technique/schedule; lung transplantation; new findings on chest radiograph at screening or within previous 90 days; AST or ALT > 5-times, or serum creatinine >2-times upper limit of normal (at screening); pregnancy; lactation; or, in the opinion of the investigator, medical or psychiatric illness interfering with study 15 participation. Efficacy Measures CFQ-R was administered at baseline and every study visit thereafter. Unless noted differently, responses to adult, teen, and child versions were combined for 20 presentation (Quittner, AL, Chest 2005; 128:2347-54). The primary efficacy endpoint was change in clinical symptoms, assessed with CFQ-R-Respiratory scores. Scores ranged from 0 to 100; increasing scores indicated improvement. In an earlier study, the minimal clinically important difference (MCID) score for the CFQ-R-Respiratory Scale was identified as five (Guyatt, GH, Med. Care 2000;I1:175-9; Jaeschke, R, Control Clin. 25 Trials 1989; 10:407-15). Thus, a five point difference in CFQ-R-Respiratory scores indicated improving/worsening symptoms. Secondary efficacy endpoints included changes in pulmonary function, hospitalizations, and non-respiratory CFQ-R Scales. Microbiological endpoints included change in sputum PA density (colony forming 30 units (CFU)/gram sputum, log 0 transformed), the minimum inhibitory concentration 57 WO 2009/045706 PCT/US2008/076431 (MIC) of aztreonam for PA, number of isolates and proportion of patients with aztreonam MIC >8 pg/ml for PA (parenteral breakpoint), and the prevalence of other pathogens. Safety Measures 5 Adverse events and changes in clinical laboratory values, vital signs, and airway reactivity were monitored. Worsening CF symptoms were treated as adverse events. Patients requiring non-study antipseudomonal antibiotics were withdrawn from the study. Statistical Analyses 10 Efficacy and safety analyses included all randomly-assigned patients receiving 1 dose of AZLI/placebo. FEVI and CFQ-R analyses used the last observation carried forward convention. A sample size of 140 was estimated to provide 77% power to detect an 8-point difference for change in CFQ-R-Respiratory scores (assuming SD=20) and to provide >90% power to detect a 9% difference in FEV (assuming SD=12), with U=0.05. 15 Continuous variables were analyzed using Analysis of Covariance (ANCOVA) models with treatment as the fixed effect; disease severity (moderate/severe) and baseline values (except for analysis of logo PA CFUs in sputum) were covariates. Changes in FEVi (liters) and changes in FEVI % predicted were analyzed using relative values; increases/decreases were calculated as percentages of the baseline FEV 1 or FEV % 20 predicted values. At Day 28, patients were categorized as improved ( 5 point increase from baseline CFQ-R-Respiratory scores), worse ( 5 point decrease from baseline) or stable/no change (<5 point change from baseline). These categories were analyzed with the Cochran-Mantel-Haenszel mean score statistic with disease severity and baseline 25 score as stratification variables Hospitalizations were analyzed using Wilcoxon rank-sum test (days) and Fisher's Exact test (proportion of patients). Aztreonam concentrations inhibiting the growth of 50% (MIC 5 o) or 90% (MIC 90 ) PA isolates and the presence of other pathogenic bacteria were summarized (Covance Central Laboratory Services, Indianapolis, IN) as were 30 plasma and sputum aztreonam concentrations (Alta Analytical Laboratory, El Dorado Hills, CA) (Burns, JL, Clin. Infect. Dis. 1998; 27:158-63). Statistical analyses were 58 WO 2009/045706 PCT/US2008/076431 performed using Statistical Analysis Software versions 8.02 and 9.1 (SAS*, SAS Institute Inc, Cary, NC). RESULTS 5 Of 253 patients screened, 164 began treatment with AZLI or placebo, 138 completed 28-days treatment, and 124 completed the study (Figure 6). Compliance with dosing ( 80% doses) was 92%. The most common reason for discontinuation during the 28-day treatment was adverse event (ALZI: 6, 7.5%; placebo: 13, 15.5%; Figure 6); most of these patients (16/19) required treatment with non-study 10 antipseudomonal antibiotics. Patient Characteristics Overall demographic characteristics appeared well balanced between treatment groups (Table 5). Mean age was 29.6 years. Most patients (127, 77.4%) were 1 8 years 15 of age. About half (93, 56.7%) were male (Table 5). At screening, 60 (36.6%) patients had FEV 1 50% predicted values and at baseline, mean FEV % predicted was 54.6%. Concomitant medications used by >40% patients at baseline included pancreatic enzymes (87%), vitamins (87%), salbutamol (79%), dornase alfa (65%), and fluticasone propionate with salmeterol 20 xinafoate (40%). Efficacy Adjusted mean CFQ-R-Respiratory scores increased from baseline values for AZLI-treated patients and decreased for placebo-treated patients (Day 28, treatment 25 difference =9.7 points; 95% Confidence Interval [CiJ=4.3, 15.1.; P<0.001; Figure 7, Table 6). By Day 42 (14 days after treatment ended), scores had declined but remained above baseline values for AZLI-treated patients, and had continued to decline for placebo-treated patients (Day 42, treatment difference =6.3 points; 95% Cl =1.2, 11.4; P=0.015; Figure 7). 30 Compared with placebo, mean CFQ-R-Respiratory scores increased for AZLI-treated patients with differing CF lung disease severity and ages (Figure 8). 59 WO 2009/045706 PCT/US2008/076431 Treatment responses were comparable for patients with moderate or severe lung disease and were larger for younger patients (<18 years) than for older patients. During treatment, CFQ-R.-Respiratory scores improved for more AZLI-treated patients than placebo-treated patients ( 5 point increase; AZLI: 45, 56%; 5 placebo: 31, 37%). Scores also worsened for fewer AZLI-treated patients ( 5 point decrease; AZLI: 20, 25%; placebo: 37, 45%; P=0.006 for overall categorical comparison). Adjusted mean FEVI increased from baseline values for AZLI-treated patients and decreased for placebo-treated patients (Day 28, treatment difference =10.3%; 10 95% Cl =6.3, 14.3; P<0.001; Figure 7). By Day 42 (14 days after treatment ended), mean FEV 1 had declined but remained above baseline for AZLI-treated patients, and had continued to decline for placebo-treated patients (Day 42, treatment difference =5.7%; 95% Cl =2.1, 9.4; P=0.002). Compared with placebo, AZLI treatment improved mean FEV values for patients with differing CF lung disease severity and ages. Treatment 15 responses were comparable for the different subgroups (Figure 8). At treatment end, changes in CFQ-R-Respiratory scores and in FEV were modestly correlated (Day 28, Pearson correlation coefficients; AZLI: 0.32; placebo: 0.32). Adjusted mean FEV 1 % predicted also increased for AZLI-treated patients and 20 decreased for placebo treated patients during treatment (Day 28, treatment difference =10.2%; 95% CI =6.2, 14.2; P<0.00l) and declined for both groups after treatment (Day 42, treatment difference =5.7%; 95% Cl =2.0, 9.4; P=0.003). Adjusted mean sputum PA density decreased for AZLI-treated patients and remained near baseline for placebo-treated patients (Day 28, treatment 25 difference = -1.453 log 0 CFU/gram; 95% CI = -2.1, -0.8; P<0.001; Figure 7). Values at Day 42 (14 days after treatment ended) were near baseline values for both treatment groups (P=0.822). There was a trend towards fewer patients being hospitalized in the AZLI group (5%) than in the placebo group (14%; Days 0-42; P=0.064) and towards fewer 30 hospitalization days (AZLI: 0.5 days; Placebo: 1.5 days; P=0.049). Compared with 60 WO 2009/045706 PCT/US2008/076431 placebo, weight increased 1.0% (Day 28, 95% Cl: 0.33, 1.69; P=0.004) for the AZLI-treated group. Responses of AZLJ-treated patients were significantly larger than those of placebo-treated patients for six of the eleven non-respiratory CFQ-R Scales; these 5 included Eating, Emotional Functioning, Health Perceptions, Physical Functioning, Role/School, and Vitality (Table 6). Safety The incidence of treatment-emergent adverse events was similar for both groups 10 during the AZLI/placebo treatment period, except productive cough was reported by significantly fewer AZLI-treated (10, 12.5%) than placebo-treated patients (21, 25%; P=0.047; Table 7). Five patients were hospitalized during the AZLI/placebo treatment period; two for respiratory symptoms (AZLI: 1; placebo: 1), two for bowel obstruction (AZLI: 1, placebo: 1) and one for umbilical hernia (placebo). Airway reactivity, defined 15 as >l5% decrease in FEVI within 30 minutes after AZLI/placebo dosing at study visits, occurred in 8 patients (AZLI: 3; placebo: 5); none of these patients withdrew for this reason. No clinically significant changes in vital signs or mean clinical laboratory values were observed except a trend in AZLI-treated patients; during the AZLI/placebo treatment period, they had fewer shifts above reference ranges than placebo-treated 20 patients for white blood cell, platelet, and neutrophil counts and neutrophil percent, all markers of systemic inflammation. There were no deaths during this study and no reports of anaphylaxis. Clinical Pharmacology and Microbiology 25 Sputum aztreonam concentrations 10 minutes postdose were (median [range]): 530 (8-6010), 677 (2-2780), and 451 (0.6-2800) pg/g sputum on Days 0, 14, and 28. Plasma aztreonam concentrations 1 hour postdose were (median [range]): 495 (0-1620), 595 (12-1660), and 603 (0-1740) ng/mL on Days 0, 14, and 28. Throughout the study, MIC 5 o and MIC 9 0 values of aztreonam for all PA isolates 30 from placebo-treated patients remained unchanged or decreased. PA isolates from AZLI-treated patients displayed a transient 4-fold increase in MICgo (Day 14). The 61 WO 2009/045706 PCT/US2008/076431 number of PA isolates with aztreonarn MIC >8 pg/mL (parenteral breakpoint) and the proportion of patients with such isolates did not increase during AZLI treatment. There was no evidence for persistent increases in Stenotrophomonas maltophilia, Staphylococcus aureus or Achromobacter xylosoxidans; B, cepacia complex was not 5 isolated. DISCUSSION Inhaled aztreonam lysine (AZLI), administered at a dose of 75 mg three times daily for 28 days to patients with moderate to severe CF lung disease and PA airway 10 infection, significantly improved respiratory symptoms and pulmonary function and significantly decreased sputum PA density, compared with placebo. AZLI was well tolerated; adverse events were generally consistent with symptoms of CF lung disease. This was the first aerosolized-antibiotic clinical study to use a patient-reported outcome (CFQ-R-Respiratory) as the primary efficacy endpoint, although a recent study 15 of hypertonic saline used it as a secondary endpoint (Elkins, MR, N. Eng. J. Med. 2006; 354:229-40; Donaldson, SH, N. Engl. J. Med. 2006; 354:241-50). CFQ-R-Respiratory scores directly measured the benefits of AZLI from the patient's perspective (Quittner, AL, Chest 2005; 128:2347-54, Goss, CH, Proc. Amer. Thorac. Soc. 2007; 4:378-86). The improvement reported for respiratory symptoms was confirmed by significant 20 improvements in FEVI and by an adverse event measure: compared with placebo, AZLI treatment decreased by half the reports of the adverse event, "productive cough." These results demonstrate that patients with CF can reliably report their symptoms using a standardized measure, and provides support for the use of patient-reported outcomes in clinical studies. However, the modest correlation between patient-reported changes in 25 respiratory symptoms (CFQ-R-Respiratory) and measured changes in lung function

(FEV

1 ) suggests they are measuring different aspects of clinical efficacy; thus a combination of patient-reported and physiological measurements may be optimal. In addition to respiratory symptoms, AZLI-treated patients reported improvements in disease-related symptoms involving eating, emotional and physical 30 functioning, health perceptions, role/school functioning, and vitality. These results have particular relevance for patients with a chronic illness, who must adhere to complex, 62 WO 2009/045706 PCT/US2008/076431 time-consuming medical regimens that affect their normal activities. Their perception of treatment benefit is likely to improve adherence to treatment regimens and influence their long-term health outcomes (Modi, AC, Pediatr Pulmonol. 2005;S28:371). CFQ-R-Respiratory scores and FEVi increased for AZLI-treated patients from 5 baseline to mid-treatment (Days 0-14), with little additional change to treatment end (Day 28). However, treatment effects continued to be observed at Day 42, 14 days after treatment ended. Adjusted mean PA density decreased throughout the 28-day AZLI treatment and returned to baseline values at Day 42. Compared with patients in the AZLI study described in Clinical Trial I, fewer 10 patients in this study used dornase alfa (65% vs. 85% patients), TIS (1.8 vs. 5.3 mean courses in previous year), and azithromycin (0% vs. 70% patients; excluded by study entry criteria). Patients in both AZLI studies had comparable lung function (FEV >25% to ;75% predicted values). This less-intensive treatment regimen may reflect a number of factors: patient intolerance to available therapies, lack of clinical response to specific 15 therapies, clinician and patient preferences, or the difficulty of obtaining TIS in some countries participating in the study. The treatment effects observed for these less intensively-treated patients (9.7 point increase for CFQ-R-Respiratory, 10.3% increase for FEVI, 10.2% increase for FEVI % predicted, 1.453 logio decrease in sputum PA density) were larger than those observed in the AZLI study described in the 20 accompanying paper (5.0 point increase for CFQ-R-Respiratory, 6.3% increase for FEVI, 6.6% increase for FEVI % predicted, 0.66 logo decrease in sputum PA density) and approached the treatment effects observed in the original TIS studies a decade ago (approximately 12% increase for FEV % predicted)(Ramsey, BW, N. Engl. J. Med, 1999; 341:23-30; Lamb, HM, Dis Manage Health Outcomes 1999; 6:93-108). 25 AZLI may provide an important new therapy for patients with CF who have moderate to severe lung disease. Further studies will be needed to define the appropriate strategy for incorporating AZLI use into the treatment of chronic PA airway infection. 63 WO 2009/045706 PCT/US2008/076431 Table 5. Patient Demographics and Baseline Characteristics* Placebo AZLI n =84 n =80 Country; n (%) US and Canada 63 (75.0) 62 (77.5) Australia and New Zealand 21 (25.0) 18 (22.5) Age, years*; mean (range) t 31.7 (11-74) 27.4 (7-54) Age group; n (%) <18 years 16 (19.0) 21 (26.3) 18 years 68(81.0) 59(73.8) Male; n (%) 45 (53.6) 48 (60.0) Weight, kg; mean (SD) 60.7 (15.2) 59.9 (17.3) Body Mass Index, kg/m 2 ; mean (SD) 21.9 (3.9) 21.4 (4.3) CFTR Genotype; n (%) Homozygous for AF508 30 (35.7) 38 (47.5) Heterozygous for AF508 22(26.2) 21 (26.3) Unidentified or Other 32 (38.1) 21 (26.3) TIS courses* in previous year; mean 1.7 1.8 Dornase Alfa use; % patients 64% 66% FEVI % of predicted value; mean (SD) 54.8 (14.0) 54.4 (13.4) Patients with FEV !50% predicted value*, n (%) 30 (35.7) 30 (37.5) CFQ-R-Respiratory score; mean (SD) 60.9 (18.9) 60.5 (18.1) MIC of aztreonarn for all PA isolates, ptg/mL

MIC

50 2 4

MIC

90 64 128 Minimum MIC 1 I Maximum MIC 256 >2048 Number of isolates tested 140 128 *At screening (Between Days -7 and -14) **TIS is not commercially available in Australia and New Zealand. Two patients from these countries reported TIS use during the previous year. t The only significant difference (P <0.05) in demographic or baseline characteristics between the two groups was in mean age, with patients in the AZLI. group being younger. However, the proportion of patients categorized as <18 versus 18 years of age was not significantly different between the AZLI and placebo groups. 64 WO 2009/045706 PCT/US2008/076431 Table 6. CFQ-R Scales: Change in Score from Baseline to End of Treatment (Days 0-28) Change from Baseline, 95% Confidence CFQ-R Scales Adjusted Mean Score Intervals P values Placebo AZLI Body Image 1.0 3.2 -2.2, 6.5 0.327 Digestion 1.9 2.2 -3.5, 4.0 0.889 Eating -4.7 3.6 4.1, 12.7 <0.001 Emotional Functioning -1.3 3.9 1.6, 8.8 0.005 H ealth Perceptions -4.8 5.0 4.8, 14.9 <0.001 Physical Functioning -6.9 2.3 3.6, 14.8 0.001 Respiratory Symptoms -2.6 7.1 4.3, 15.1 <0.001 Role/School -4.2 2.1 1.3, 11.4 0.014 Social Functioning -3.6 -1.2 -1.7, 6.5 0.248 Treatment Burden -3.1 0.2 -1.5, 7.9 0,177 Vitality -4.4 3.6 2.5, 13.5 0.005 Weight 1.4 4.7 -4.0, 10.5 0.376 65 WO 2009/045706 PCT/US2008/076431 Table 7. Treatment-Emergent Adverse Events (TEAEs) Reported by 5% Patients in Either Treatment Group during the AZLI/placebo Treatment Period Placebo AZLI TEAEs*, n (%) n=84 n=80 Cough 25 (29.8) 28 (35.0) Productive Cough** 21 (25.0) 10 (12.5) Pharyngolaryngeal Pain 7 (8.3) 10 (12.5) Nasal Congestion 8 (9.5) 8 (10.0) Pyrexia 4 (4.8) 7 (8.8) Crackles Lung 6 (7.1) 6 (7.5) Headache 10 (11.9) 5 (6.3) Dyspnoea 8 (9.5) 5 (6.3) Wheezing 7 (8.3) 5 (6.3) Chest Discomfort 4 (4.8) 5 (6.3) Throat Irritation 2 (2.4) 5 (6.3) Fatigue 7 (8.3) 3 (3.8) Pulmonary Function Test Decreased 6 (7.1) (3.8) Abdominal Pain 6 (7.1) 2 (2.5) Haemoptysis 6 (7.1) 2 (2.5) *TEAEs coded using the Medical Dictionary for Regulatory Activities (MedDRA, Version 8.0) preferred term. 5 **Significantly fewer in AZLI group (P =0.047), Fisher's Exact Test; tested if TEAB incidence !10% in either treatment group. Clinical Trial III 10 Study CF-A(-006: This is an ongoing open-label, multicenter study evaluating the safety and efficacy of repeated AZEI exposure in CF patients who participated in either Clinical Trial I or Clinical Trial 11 described above. Patients receive up to nine 28-day courses of Al in the same regimen, BID or TID, to which they were assigned in either Clinical Trial 15 1 or Clinical Trial 11. Each course of AZLI is followed by a 28-day off drug period. Patients must have completed Clinical Trial I or Clinical Trial 11 or have been withdrawn due to need for antipseudomonal antibiotics or due to an adverse event (AE) unrelated to study medication intolerance. During the study, patients may be treated as needed with any antipseudomnonal antibiotics (oral, IV, or inhaled) with the exception of IV 20 aztreonam. At the 01 March 2007 interim data cut-off, 207 patients had been enrolled and had at least one post -enrollm nent visit. There are 82 patients in thle Al BID group and 125 in the Al TID group. The safety profile observed over the first three courses was 66 WO 2009/045706 PCT/US2008/076431 consistent with the expected symptoms of the patients' underlying CF lung disease. Respiratory symptoms were the predominant cause of AE reports. No differences were observed between regimens in the overall rates of AEs, drug-related AEs, or significant adverse events (SAEs). There was little change in susceptibility of PA to aztreonam 5 during the trial. In both the BID and TID treatment groups, the MIC 5 remained unchanged (+ 2-fold change) from Visit 1, while transient increases in the M1C 90 were observed. Following completion of each of the first three courses of AZLI, the absolute mean change from baseline in CFQ-R respiratory symptoms domain scores was greater in the TID group compared to the BID group. Similarly, FEVi ([L] and % predicted) was 10 improved relative to baseline after each 28-day course of AZLI, with group means returning to baseline at the end of the 28-day follow-up period (prior to the next course of AZLI). The percent change from Visit 1 in FEV 1 was higher in the TID than the BID group at the end of each of the first three AZLI courses. The percent change from Visit I remained higher in the TID group at Visit 6, compared to the BID group, but was not 15 statistically significant. PA sputum density decreased relative to baseline in both groups during treatment; the decreases were consistently larger among TID-treated than BID treated patients. Mean Change in CFQ-R Respiratory Symptoms Domain Scores from Day 0: In the open-label follow on study, the mean CFQ-R respiratory symptoms 20 domain scores at baseline (Visit 1) were approximately 66 and 62 for the BID and TID groups respectively. Mean (standard deviation (SD)) change in CFQ-R respiratory symptoms domain score after the first 28 days of open-label therapy was 3.53 (12.53) for the BID group and 7.06 (16.35) for the TID group This change is consistent with that observed after 28 days of AZLI therapy in the controlled trials. Table 8 shows change in 25 CFQ-R respiratory symptoms domain scores from Day 0 of the open-label trial to the end of the first three open-label AZLI courses and the last attended visit of the open-label trial . 67 WO 2009/045706 PCT/US2008/076431 Table 8. Mean Change in CFQ-R Respiratory Symptoms Domain Scores from Day 0 to End of Treatment Courses--Open-label Trial Al BID (N =82) Al TID(N = 125) End Course I (Day 28) n 78 124 Mean (SD) 3.53 (12.53) 7.06 (16.35) Median 5.56 5.56 Range -38.9 -27.8 -38.9 - 72.2 End Course 2 (Day 84) 11 75 106 Mean (SD) 2.93 (13.98) 6.39 (16.46) Median 0.00 5.56 Range -50.0 - 33.3 -38.9- 55.6 End Course 3 (Day 140) n 69 88 Mean (SD) -0.16 (19.78) 7.45 (19.01) Median 0.00 5.56 Range -61.1 -33.3 -44.4-50.0 Last Attended Visit n 79 124 Mean (SD) 0.84 (16.29) 4.03 (19.60) Median 0.00 2.78 Range -61.11 - 44.44 -61.11 - 66.67 5 Figure 9 compares the mean change in CFQ-R respiratory symptoms domain scores observed from baseline to Day 28 in the controlled trials to that observed from the first day to last day of each of the first three AZLI treatment courses (ie, within each 28 day interval) in the open-label trial. Note that the data in Figure 9 are change within courses and therefore do not match Table 8. The change in mean CFQ-R respiratory 10 symptoms domain scores observed during the TSI run in period of Clinical Trial I are also shown for comparison. Mean Change in CFO-R Respiratory Symptoms Domain Scores from Day 0 Qf Open label Follow-on-Trial by Previous Study: 68 WO 2009/045706 PCT/US2008/076431 Table 9 shows mean change in CFQ-R respiratory symptoms domain scores from Day 0 of Clinical Trial III by previous study. At the completion of each of the first three open-label AZLI treatment courses, mean changes were greater for patients from Clinical Trial 11 than for patients from of Clinical Trial L 5 Table 9. Mean Change in CFQ-R Respiratory Symptoms Domain Scores from Day 0 of Open Label Trial by Previous Trial (Observed Case Data) Clinical Trial I Clinical Trial II Al BID Al TID Al Pooled A[ TID (N = 82) (N = 74) (N = 156) (N =51) End Course 1 (Day 28) n 78 73 151 51 Mean (SD) 3.53 (12.54) 7.61 (15.78) 5.50 (14.93) 6.26 (17.26) Median 5,56 5.56 5.56 5.56 Range -3 8.89 - 27.78 -33.33 - 66.67 -38.89 - 66.67 -38.89 - 72.22 End Course 2 (Day 84) n 75 67 142 39 Mean (SD) 2.93 (13.98) 4.39 (16.00) 3.62 (14.93) 9.83 (16.88) Median 0.00 5.56 0.00 11.11 Range -50.00 - 33.33 -38.89 - 55.56 -50.00 - 55.56 -33.33 - 55.56 End Course 3 (Day 140) n 70 59 129 29 Mean (SD) 0.08 (19.74) 6.36 (20.56) 2.95 (20.28) 9.67 (15.48) Median 0.00 0.00 0.00 5.56 Range -61.11 - 33.33 -44.44 - 50.00 -61.11 - 50.00 -22.22 - 50.00 10 Categorical Change in CFQ-R Respiratory Symptoms Domain Scores: Table 10 shows the categorical change in CFQ-R respiratory symptoms domain scores over the first three AZLI courses in Clinical Trial 111; change is from Day 0 of the open-label trial. At the end of the first three courses, the proportion of patients with improvement in symptoms was approximately 20% greater than the proportion with 69 WO 2009/045706 PCT/US2008/076431 worsening of symptoms. A greater proportion of patients in the TID than BID group had improved symptoms. Table 10. Categorical Change in CFQ-R Respiratory Symptoms Domain Scores First Three AZLI Courses of Open-label Follow on Trial AZLI BID AZLI TID AZLI Total (N = 82) (N = 125) (N = 207) n(%) n (%) n(%) End Course I (Day 28) n 78 124 202 Improved 40(51.3) 79(63.7) 119(57.5) Stable or no change 22(28.2) 13(10.5) 35 (16.9) Worsened 16 (20.5) 32 (25.8) 48 (23.2) End Course 2 (Day 84) n 75 106 181 Improved 33 (44.0) 61 (57.5) 94 (51.9) Stable or no change 22 (29.3) 21(19.8) 43 (23.7) Worsened 20 (26.7) 24 (22.6) 44 (24.3) End Course 3 (Day 140) n 79 88 157 Improved 32(46.4) 49 (55.7) 81 (51.6) Stable or no change 13 (18.8) 17(19.3) 30(19.1) Worsened 24 (34.8) 22 (25.0) 46 (29.9) 5 Improved - increase in score of 5 Stable or no change - change of less than 5 (increase or decrease) Worsened - decrease in score of 5 10 Open-label Follow On Trial Mean Relative Change in FE 1 %predicted: Table 11 shows mean relative change in FEV, % predicted from Day 0 to the end of each of the first three A] treatment intervals of the open-label trial. There was positive FEV, response noted at the end of each treatment course; a consistently greater response 70 WO 2009/045706 PCT/US2008/076431 was observed in the TID arm. These results are supportive of those observed during the controlled trials. Table 11. Mean Relative Change in FEVi % Predicted from Day 0-Open-label Trial AZLI BID AZLI TID (N = 82) (N = 125) End Course I (Day 28) n 80 122 Mean (SD) 4.10 (10.48) 9.85 (17.27) Median 3.61 6.94 Range -17.71 - 36.34 -25.26 - 108.86 End Course 2 (Day 84) n 75 107 Mean (SD) 2.40 (8.89) 8.65 (19.00) Median 3.18 6.02 Range -16.74 - 23.86 -44.08 - 110,48 End Course 3 (Day 140) n 71 90 Mean (SD) 2.63 (11.47) 6.86 (18.27) Median 3.61 4.93 Range -32.24 - 28.76 -37.91 - 93.83 5 Figure 10 shows the FEVi response within each of the first three AZL treatment courses in the open-label trial. The relative change in FEVI % predicted observed during the treatment periods of the Phase 3 controlled trials, as well as that for the TSI run in period of Clinical Trial I is presented for comparison. 10 Mean Percent Change in FEV (L): Table 12 presents results for mean percent change in FEVI (L). There are no meaningful differences between these results and those for mean relative change in FEVi % predicted. 71 WO 2009/045706 PCT/US2008/076431 Table 12. Mean Percent Change in FEV 1 (L) from Day 0-Open Label Trial AZLI BID AZLI TID (N = 82) 1.(N 125) End Course I (Day 28) n 80 122 Mean (SD) 4.05 (10.27) 9.86 (17.27) Median 3.71 6.99 Range -17.50 - 33.33 -25.13 - 108.74 End Course 2 (Day 84) n 75 107 Mean (SD) 2.43 (8.85) 8.66 (18.98) Median 3.50 5.48 Range -16.86 - 23.68 -44.16 -110.16 End Course 3 (Day 140) n 70 97 Mean (SD) 2.72 (11.51) 6.76 (18.22) Median 3.59 4,41 Range -31.74 - 28.37 -37.57 - 93.20 5 Mean Relative Change in FEV, % predicted by Previous Study: Table 13 presents mean relative change in FEVi % predicted during the first three courses of the open-label study by previous trial. Positive FEVi response was observed 10 during each course in patients from both studies; the TID arm had a consistently larger response than the BID arm in Clinical Trial 1. Patients from Clinical Trial 11 had greater improvement in FEV 1 % predicted during each treatment courses than did patients from either the BID or TID arms of Clinical Trial I. 72 WO 2009/045706 PCT/US2008/076431 Table 13. Mean Relative Change in FEV 1 % Predicted by Previous Study-Open label Trial 5 Clinical Trial I Clinical Trial 11 AZLI BID AZLI TID AZLI Pooled AZLI TID (N = 82) (N = 74) (N = 156) (N = 51) End course I (Day 28) n 80 72 152 50 Mean (SD) 4.10 (10.48) 8.93 (16.18) 6.39 (13.65) 11.19 (18.81) Median 3.61 6.55 4.99 7.92 Range -17.71 - 33.34 -25.26 - 66.56 -25.26 - 66.56 -13.85 - 108.86 End course 2 (Day 84) n 75 67 142 40 Mean (SD) 2.40 (8.89) 5.32 (13.65) 3.78 (11.44) 14.23 (24.78) Median 3.18 4.39 3.76 7.32 Range -16.74 - 23.86 -44.08 - 47,00 -44.08 - 47.00 -22.11 - 110.48 End course 3 (Day 140) n 71 60 131 30 Mean (SD) 2.63 (11 47) 3.54 (15.00) 3,04 (13.16) 13.51 (22.32) Median 3.61 2.08 3.17 7.78 Range -32.24 - 28.76 -37.91 - 42.22 -37.91 - 42.22 -11.17 - 93.83 Mean Percent Change in FEV (L) by Previous Study: Table 14 presents data for mean percent change in FEV (L) by previous study. 10 There are no meaningful differences between these results and those for mean relative change in FEV 1 % predicted (See Table 13). 73 WO 2009/045706 PCT/US2008/076431 Table 14. Mean Percent Change in FEV (L) by Previous Study-Open Label Trial Clinical Trial I Clinical Trial 11 AZLI BID AZLI TID AZLI Pooled AZLI TiD (N = 82) (N = 74) (N = 156) (N = 51) End Course 1 (Day 28) n 80 72 152 50 Mean (SD) 4.05 (10.27) 8.93 (16.21) 6,36 (13.59) 11.20 (18.78) Median 3.71 6.60 4.93 7.95 Range -17.50 - 33.33 -25.13 - 66.47 -25.13 - 66.47 -13.89- 108.74 End Course 2 (Day 84) n 75 67 142 40 Mean (SD) 2.43 (8.85) 5.35 (13.72) 3.81 (11.46) 14.22 (24.69) Median 3.50 4.26 3.60 7.17 Range -16.86 - 23.68 -44.16 - 48.00 -44.16 - 48.00 -22.11 - 110.16 End Course 3 (Day 140) n 71 60 131 r 30 Mean (SD) 2.72 (11.43) 3.56 (15.04) 3.11 (13.16) 13.14 (22.25) Median 3.33 2.26 3.00 6.21 Range -31.74 -28.37 -37,57 - 41.84 -37.57 - 41.84 -11.43 - 93.20 5 Discussion The most important efficacy endpoint for the clinical development program, change in CFQ-R respiratory symptoms domain scores, measured patient perception of 10 change in their respiratory symptoms. This endpoint showed a significant difference between AZLI and placebo groups in both studies. At both Days 14 and 28, the treatment differences for Clinical Trial 11 (7.98 and 9.71) and Clinical Trial 1 (5.53 and 5.01) demonstrated a clinically significant improvement in respiratory symptoms among AZLI treated patients compared to placebo; this improvement persisted through Day 42 in study 15 Clinical Trial I. A change of five points represents the minimum change that can be detected by an individual patient. Furthermore, significantly greater percentages of patients receiving AZLI compared to placebo had scores indicating improvement in respiratory symptoms, and a lower percentage had worsening symptoms at Days 14 and 74 WO 2009/045706 PCT/US2008/076431 28. Similar results have been observed in the ongoing open label trial, with larger change scores for patients who rolled over from Clinical Trial II; some attenuation of response is observed in the second and third AZLI courses among patients from study Clinical Trial 1; but an analysis of the combined trials shows a sustained response. Among AZLI 5 treated patients, increases in CFQ-R respiratory symptoms domain scores were greater among patients with baseline FEV >50 % predicted, females, and those from outside the US. The finding that females had greater improvement in CFQ-R scores was not unexpected. Gender differences have been well documented in CF patients, with females historically having poorer outcomes, but stronger response to therapy, as demonstrated in 10 the TSI registration trials. Consistent with the observed improvement in respiratory symptoms and reduction in antibiotic use, two key markers traditionally used to evaluate the efficacy of antibiotic therapies in CF, change in pulmonary function and PA density in sputum, demonstrated a significant advantage for AZLI treated patients. By Day 14 of AZLI 15 treatment in both controlled trials, FEV ([L] and % predicted) had improved significantly compared to placebo. At Day 28, the treatment differences between the AZLI and placebo groups for mean percent change in FEVi (L) were 6.3% (Clinical Trial I) and 10.3% (Clinical Trial II), respectively; the difference between groups for relative change in FEVi % predicted were 6.6% and 10.2%. These results compare favorably with 20 the treatment effect observed in the registration trials for TSI and Pulmozyme, as well as a European trial comparing inhaled tobramycin and colistin (See Table 15). Moreover, these improvements were maintained through Day 42, 14 days after the end of AZLI treatment, whereas FEV response in the TSI trials peaked at Day 14 and declined thereafter. The treatment effect in Clinical Trial I is noteworthy in that these patients had 25 received a 28 day TSI course immediately prior to AZLI therapy; the minimal improvement (0.9%) observed during the TSI run in period would not predict that a robust increase in pulmonary function could be achieved within 14 days of AZLI therapy. FEVI response in the first three courses of the open label trial show consistent improvements over baseline. As observed for the change in patient perception of 30 symptoms, patients who rolled over from Clinical Trial 11 had more pronounced FEVi response in the open label trial; by the end of the third course (6 months after beginning 75 WO 2009/045706 PCT/US2008/076431 open label treatment), improvement in FEV I % predicted (13.5%) was greater than after the end of the first course (12.0%); and the open label results for patients from Clinical Trial III contrasted sharply with the negligible change in FEV 1 % predicted observed during the TSI run in phase of Clinical Trial 1 (0.9%). This is also greater than the 5 improvement observed at the end of the third TSI course (10%) of the TSI registration trials. Greater improvements in FEVI were observed for patients with less severe baseline disease and more susceptible PA isolates, as well as those from outside the US. The finding of comparable FEV, response for AZLI treated patients of all age groups 10 differ from the TSI registration trial results where response among patients 13 to 17 years was significantly greater than among younger or older patients. Reduction in PA CFU density mirrored increases in pulmonary function during the 28 day treatment course, with significant decreases for AZLI treated patients in both studies observed within 14 days of the start of treatment. At Day 14, the treatment 15 differences for Clinical Trial I and Clinical Trial II were 0.49 and 0.88 log 0 , respectively, by Day 28 the treatment differences between groups increased to 0.66 log10 and 1.45 logo. The magnitude of these reductions is comparable to those observed in studies of inhaled tobramycin and colistin, including the TSI registration trials (See Table 15). Following cessation of treatment, CFU density increased and by Day 42, although 20 respiratory symptoms and pulmonary function still showed improvement over baseline for AZLI treated patients, CFU density was near, or exceeded, baseline values. In the open label follow on trial, CFU density decreased during each of the first three 28 day courses, but the magnitude of the reductions was not as great as at Day 28 of treatment in the controlled trials. These results are consistent with those from the TSI registration 25 trials, where there was a reduced effect in later treatment courses. The smaller reduction observed between days 0 and 28 in Clinical Trial I may be attributed to the TSI treatment during the run in phase, as prior antibiotic treatment may attenuate CFU response. Reductions in CFU density were larger for AZL1 treated patients with less severe disease, more susceptible PA isolates, males and patients under 18 years of age; this latter result is 30 consistent with the TSI trials which showed decreased CFU response with increasing age. 76 WO 2009/045706 PCT/US2008/076431 Table 15. Relative Change in FEV from Baseline in Previous Studies Baseline Pulmonary Fein PA Density Study Function Entry FEV 1 Change Change Criteria Predicted (mg)/Du ration(L 1 ) (mean±SD)S Tobranycin FVC > 40% 55 3.7 to 600 TID %OW -2.0 (N=36) 60 ±3.2 (N=258) FEV, 25-75% 49.9 ± 15.5 300 BID/28 12% -2.0 Adolescents FEVi 25-75% unk 300 BID/28 ~1 6 %b not (N=63)' days evaluated Adults FEV125-75% unk 300 BID/28 ~6%' not (N=140)' days evaluated TOBI (N=53) FEV i 2 25% 55.4 ± 22.9 300 BID/28 7 %' -0.9 days Colistin 2 FEV, 25% 59.4 22.6 80 BID/28 0 % -0.6 (N=62) days Pulmozyme' FVC > 40% 61.1±26.9 2.5 mg BID/24 5.8±0.7c not weeks evaluated Pulmozyme FVC > 40% 60.0 2.69 2.5 mg TID/24 5.6±0.72 not weeks evaluated a Absolute change in FEVI % predicted, comparison to control after 28 days of therapy 5 b Relative change in FEV % predicted, comparison to control after 28 days of therapy c Percent change in FEVI (L), comparison to control after 24 weeks of therapy d FEV 1 change is relative change compared to control at 28 days 10 In addition to showing improvement in respiratory symptoms, the CFQ-R demonstrated improvements in non-respiratory domains of physical functioning, emotional functioning, body image, eating disturbances, role limitations/school performance, weight disturbances, vitality, and treatment burden. These results have particular relevance for patients with a chronic illness, who must adhere to complex, 15 time-consuming medical regimens that affect their normal activities. Their perception of treatment benefit is likely to improve adherence to treatment regimens and influence their long-term health outcomes. Increases in weight and body mass index in patients treated with AZLI vs. placebo provided additional confirmation of the general health benefit derived from 20 AZLI therapy during these trials. 77 WO 2009/045706 PCT/US2008/076431 It is important to note that therapeutic benefit was demonstrated in all subgroups defined by age, baseline disease severity and PA susceptibility, and gender and that similar results were obtained from three trials which can be viewed as bracketing the current standard of care for CF lung disease (i.e. Clinical Trial II = therapy in patients off 5 antibiotics for 28+ days, Clinical Trial I = therapy in extensively treated patients immediately following a 28 day TSI course, and Clinical Trial III = therapy in patients currently treated as clinically indicated). The above embodiments represent certain aspects of the invention. Additional objects, aspects and embodiments would be apparent to one skilled in the art and are 10 intended to be encompassed by the instant invention. All references cited in the instant application are incorporated by reference herein in their entirety. 15 78

Claims (17)

1. The use of a therapeutically effective amount of an inhalable dry powder or aerosol comprising about 1 to about 250 mg of aztreonam lysine per one dose in the 5 manufacture of a medicament for treating at least one health-related quality-of-life symptoms of a lung disease in a patient in need thereof wherein said inhalable dry powder or aerosol is administered to the airways of the lung using a dosing regimen comprising administering said inhalable dry powder or aerosol for at least 14 to 28 consecutive days followed by a 14 to 28 day drug holiday and repeating the regimen at 10 least one time.

2. The use of claim I wherein a dose of inhalable dry powder or aerosol is administered 3 to 10 times a day. 15

3. The use of claims I or 2 wherein the patient has a pulmonary bacterial infection caused by gram-negative bacteria.

4. The use of claim 3 wherein the pulmonary bacterial infection is Pseudomonas aeruginosa. 20

5. The use according to any one of claims I to 4 wherein the lung disease is cystic fibrosis.

6. The use of claim 5 wherein the health-related quality-of-life symptom is one, two, 25 three, four, five, six, seven, eight, nine, ten, eleven or all of the domains of the Cystic Fibrosis Questionaire-Revised.

7. The use of claim 6 wherein the domain is selected from the group consisting of the respiratory domain, the body image domain, the digestion domain, the eating domain, 30 the emotional domain, the health perceptions domain, the physical domain, the 79 WO 2009/045706 PCT/US2008/076431 role/school domain, the social domain, the treatment burden domain, the vitality domain, and the weight domain.

8. The use of any one of claims I to 7 wherein the inhalable aerosol comprises about 5 1 to 250 mg of aztreonam lysine per one dose dissolved in about I to about 5 mL of a saline solution comprising about 0.1 to about 0.45%, w/v, of sodium chloride.

9. The use of any one of claims I to 8 wherein the inhalable aerosol is delivered by an electronic nebulizer adapted to deliver predominantly aerosol particle sizes comprising 10 mass median aerodynamic diameters of about I to about 5 in.

10. The use of any one of claims I to 9 wherein a dose of inhalable aerosol is administered three times a day. 15

11. The use of any one of claims I to 10 wherein each inhalable aerosol dose comprises about 75 mg of aztreonam dissolved in about I mL of saline comprising about 0.17%, w/v, sodium chloride.

12. The use of any one of claims I to 11 wherein the administration of the inhalable 20 aerosol during the first dosing regimen is preceded by a standard prescribed 28 day administration of tobramycin inhalation solution.

13. The use of any one of claims I to 12 wherein the regimen is repeated one to nine times. 25

14. The use of any one of claims 6 to 13 wherein, during at least one dosing regimen, the respiratory domain score after an inhalable aerosol administration is increased by at least 5 points compared to the score at the beginning of the regimen. 30

15. The use of any one of claims 6 to 14 wherein, during at least one dosing regimen, the respiratory domain score following the inhalable aerosol administration remains 80 WO 2009/045706 PCT/US2008/076431 increased compared to the beginning of the regimen after a patient's Pseudomonas aeruginosa sputum density during the drug holiday of the regimen has increased to at least the density at the beginning of the regimen. 5

16. The use of any one of claims 6 to 15 wherein the regimen is repeated at least three times and wherein, after the second regimen, the respiratory domain score after any one regimen does not decrease to the score at the beginning of the first regimen.

17. A use or method as claimed herein. 10 81